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SUMMARY OF OPENING STATEMENT

by
Director, National Institutes of Health

COMMITTEE ON APPROPRIATIONS
1961 ESTIMATE

Mr. Chairman and Members of the Committee:

Once again it is my pleasure to appear before you in con-
nection with the Public Health Service appropriations that
finance the program and activities of the National Institutes
of Health.

The present statement offers certain general considera-
tions that relate to total activities of NIH 3 It also introduces
separate statements on the Division of Biologies Standards,
Division of General Medical Sciences, and central services in
support of the Institutes' programs.

Let me say at the outset that the additional funds made
available to us by the Congress for 1960 have been used to good
advantage in the conduct and support of research projects, train-
ing programs, and research construction in the health field.

A view of 1960 activities in broad perspective reveals that
these programs have matured and become established and essential
parts of the Nation's medical research effort while assuring the
freedom and integrity of the grantees and their institutions. On
the other hand, the needs of the institutions themselves are not
being met. The universities, medical schools, and other centers
for health research and teaching evince difficulty in financing
with balance their traditional missions — research, education, and
public service.

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The broader our programs, the more deeply they become in-
volved in support of the educational process. This implies an
obligation to help the institutions sustain initiative. Grants
enabling schools to experiment with ways of producing medical
scientists are a step toward support of the educational process
itself.

The current NIH program reflects our concern over institu-
tional strength and stability in (1) a trend toward larger grants
for more broadly defined objectives, (2) strong fellowship and
training programs, (3) an adjustment in the starting dates of
training grants, (4) a proposal to provide for the full indirect
costs of grantee research, (5) a proposal to award institutional
research grants, and (6) development of clinical, therapeutic and
metabolic research centers and primate colonies.

Appraisals of NIH programs were made throughout the past
year. These included the participation of nearly 700 nonfederal
scientists and leaders in public affairs whose recommendations
govern the grant and award programs; the reviews of our own research
activities at Bethesda by distinguished consultants; and the
responses of grantees, interested agencies, and the general pub-
lic. There have also been several special appraisals by Federal
groups: (1) advisors to the Senate Appropriations Committee
assessing our current operations, (2) the General Accounting Office
reviewing extramural programs, (3) the Appropriations Committee
of the House of Representatives auditing certain programs and
procedures, (4) the Office of the Surgeon General conducting

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related studies on health manpower and environmental health
hazards, (5) the NIH task force of Dr. Kenneth M. Endicott
studying the impact of NIH grant programs on medical schools, and
(6) two units newly established within our Division of Fesearch
Grants, one to facilitate program anlaysis and review, and the
other to provide a central focus for training grants.

The 1960 Appropriation Act contained increases of $115.8
million over the NIH total for 1959. In our apportionment
request, which was approved by the Bureau of the Budget, we pro-
jected an unexpended balance of $5.85 million. As of this date,
this would appear to be a relatively accurate estimate. It is
possible, however, that when the February /March Council meetings
are completed, this estimate may change.

Ten substantive highlights of the 1960 NIH program may be
cited. Advances were made in (1) collaborative studies of peri-
natal disease, (2) the cancer chemotherapy program, (3) collabora-
tive studies in psychopharmacology, (4) the field of viruses and
cancer, (5) the development of a program in mathematics and
physical biology, (6) activities concerning the development of a
live-virus polio vaccine, (7) new construction at Bethesda, (8)
programs to support research in other countries and exchange of
scientists and scientific information, (9) the establishment of
programs for training in basic sciences, and (1) the program of
grants to assist in the construction of health research facilities „

Thus far in 1960, research grant applications have been re-
viewed in unprecedented number — 7,975. But an increase in the num-
ber of Study Sections to 33 has enabled us to keep pace.

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Special review procedures have been established in compliance
with the President's criteria seeking to help avoid the hazards
of rapid program growth. Some 64 grant applications approved
in June were denied support when reexamined in October. But
the volume of new applications has continued to rise, and the total
number recommended for approval has not decreased. High standards
of review have been maintained despite the rapid increase in ap-
propriations .

The individual witnesses will introduce detailed state-
ments of research and program highlights related to NIH appropria-
tions for 1959.

In the President's 1961 budget request, the proposed NIH
appropriations total $426.7 million. Included is a $5 million
reduction below the authorized $30 million under the Health
Research Facilities Construction Act. The Department, however, is
considering legislation that would make similar matching grants
available for construction of facilities not only for research
but also for teaching. Also included in our budget request are
increases in funds for research and for development of certain
animal facilities.

Forces that may be expected to shape future trends in NIH
programs include (1) greater attention to the development of
research resources and to mechanisms permitting more stability
in research careers, (2) modifications in research support which
will strengthen the institutions as such, (3) decentralization of
some processes for determining the support of research and training,
and (4) application of new techniques and disciplines, enabling
research to probe deeper into the unknown.

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OPENING STATEMENT
by
Director, National Institutes of Health
COMMITTEE ON APPROPRIATIONS
1961 ESTIMATE

Mr. Chairman and Members of the Committee:

Once again it is my pleasure to appear before you in connection
with the Public Health Service appropriations that finance the programs
and activities of the National Institutes of Health.

A familiar face is missing from our group of witnesses, Mr. Chairman.
I refer to Dr. C. J. Van Slyke, who retired from the Public Health Service
last December after nearly thirty years of dedicated service to medicine
and public health. During the last half of his career, Dr. Van Slyke was
the primary architect and builder of the research, training, and
construction grants through which the Institutes now support a large
part of the Nation's total medical research effort. Our grant and
awards programs reflect Dr. Van's basic conviction that Federal funds
can be provided under terms that permit the individual freedom of
inquiry, that support institutions in the achievement of their own goals,
and that at the same time focus in a very direct sense on the immediate
health needs of the American people. I know the Committee will miss
having him here, as we do.

Dr. Van Slyke 1 s work is now being carried out by Dr. Kenneth M.
Endicott, who is here today. Dr. Endicott has had a series of increas-
ingly responsible positions at NIH, including that of laboratory scientist
in chemistry and pharmacology, Scientific Director of the Division of

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Research Grants, Director of the Cancer Chemotherapy Program from
its inception until it became an established and unified research
activity, and most recently Associate Director of NIH with special
emphasis on our training grants and awards.

It is my purpose to place before you certain general considerations
that relate to the total activities of the National Institutes of Health.
It is also my purpose to provide the Committee with more specific
information concerning the two programs- -the Division of General Medical
Sciences and the Division of Biologies Standards- -that are financed under
the appropriation entitled "General Research and Services, NIH,'" as well
as our activities under a management fund through which certain services
are provided centrally in support of all of the Institutes and operating
programs. I have with me prepared statements on each of these three
topics. I shall be glad to submit them for the record at the conclusion
of my general remarks, or to handle them in whatever other way the
Committee may wish.

Let me say at the outset that the additional funds made available
to us by the Congress for i960 have been used to good advantage in the
support of projects of high quality. Scientists, scientific institutions,
and the people as a whole have reason to be grateful for the part played
by the Congress in supporting medical research as a sound investment in
America's future. It is our primary role at NIH to serve as custodians
of these funds derived from taxes, appropriated by the Congress, and used

to conduct and support current research; research; academic, and service
training, and research construction in the health field. This is not a
passive role: we find it creative and challenging and most rewarding,
and like the scientists and scientific institutions supported under
our grants and awards programs, we too have good reason to acknowledge
this Committee's interest and affirmative action on medical research
matters that have such an intimate relationship to the Nation's health.

PERSPECTIVE ON i960 ACTIVITIES
i960 has been a year in which the strengths and limitations of
our medical research support processes have stood out in sharp focus.

The strengths are derived from the increasing maturation of
programs that at their inception were sound in principle and have now
Decome established and essential parts of the Nation's medical research
effort. These programs began with our own traditional research activity
in Bethesda, to which breadth and depth were added as new Institutes and
new facilities were brought into being. Grant support of the research
projects of nonfederal scientists was initiated in 19^6. Programs to
develop manpower and facilities resources followed thereafter. Elabora-
tions and refinements of our support mechanisms have been accompanied by
rapid increases in annual appropriations for these purposes. Today, our
programs support more than one -third of all medical research in this
country. Thousands of young men and women are being aided while they

complete their postgraduate training for research, academic, and

service careers. And hundreds of research laboratories are being constructed

or renovated, in part with matching grants from our appropriations.

In essence, those aspects of our programs that provide current
support for individual research projects and assistance to talented
individuals during their advanced training- -programs which together
represent more than 85 percent of our I960 activities- -pose no major
problems of either a policy or an operating nature. There will of
course continue to be questions to be answered and adjustments to be
made as to the level, direction, and emphasis in these established pro-
grams. But the primary task, that of developing effective means for
Federal funds to share in the support of individual research projects
and postgraduate training while at the same time assuring the freedom
and integrity of the grantees and their institutions, is behind us.

It is my belief, at this point in time, that these established
and accepted activities in support of the individual should continue
to be the central focus of our programs.

NEEDS OF GRANTEE INSTITUTIONS
On the other hand, there is abundant evidence today that although
many of the specific needs of the individual and of the individual fields
of science are being met, the needs of the grantee institutions are not
being met. The universities, medical schools, and other centers for

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research and teaching in the health sciences serve the people in three ways:
in research, in education, and in public service. Their institutional needs
are overwhelming, and the means for satisfaction of those needs are
inadequate .

The point may be made that if the Nation's system of educational
and research institutions were financially capable of doing so, they
c ould :

1. Provide a stable background for current activities supported
by outside funds.

2. Extend research to include opportunities newly apparent to the
medical investigator --ranging from the active entrance of
university sciences (such as mathematics, chemistry, and physics
on the one hand and genetics, developmental and systematic
biology, andosocial anthropology on the other) to the
development of modern epidemiology in the design of studies of

a demographic nature as an essential area of proper study in
the causation of chronic illness.

3- Provide an organizational structure for the grouping of diverse
disciplines and approaches centered about broad disease
categories, without at the same time distorting the fundamental
structure and function of the institutions of higher learning.

The inability of our system as a whole to do any of these things
adequately and in a balanced fashion is clear. This gives rise to concern
about the financial capacity of our academic institutions as they look
to the challenges before them and the Nation.

As NIH programs are broadened to encompass activities such as
extensive training programs, they inevitably affect the educational
process. This is also true when support of research is broadened,

as it has been, to the point where the whole institution is involved.

NIH programs not only influence the educational process, but also directly

support part of it.

The Congress, and all others who present, support, or act upon our
appropriation requests, should understand fully that the broader our
programs are, the more deeply they become inevitably involved in support
of the educational process. This direct involvement places upon the NIH
the obligation to help the institutions sustain the initiative to develop
their own objectives. This has been done through grants enabling schools
to experiment with ways of producing medical scientists. More will be
done along this line as NIH activities continue to extend beyond support
of research and training to support of segments of the educational
process itself.

Finally, in presenting our programs to the Congress, we will
present proposals for improving the mechanisms, and the terms and conditions,
through which support for research and training is provided. The ways
in which funds are made available affect the productivity of investigators,
and are therefore as important as the dollar level of support and the kind
of research which is aided.

For an activity such as ours, with focus on support of the
research component of nonfederal institutions, there is an obligation
to provide such support under terms and conditions which recognize
and seek to ameliorate the institutions' dilemma, or at the very least

do not increase their already pressing problems.

There are a number of vays in which the i960 NIH program and the
1961 proposal reflect our concern over institutional strength and
stability.

1. The research project grants, without deviation from standards
of excellence, continue to follow a trend towar d larger grants f or more
broadly defined objectives , with support committed for longer periods

of time. This trend is the product of the changing nature of scientific
endeavor and the significant increase in the funds available, but it has
positive value to the stability of the institutions where the research is
carried. out.

2 . The fellowshi p and training grants and a wards programs , extend-
ing into new fields and utilizing new mechanisms during a period of rapid
expansion, have contributed in a very direct sense to the total strength
of grantee institutions. Our programs are centered on increasing the
number and quality of manpower; but both the teaching and the public
service aspects of the schools are enhanced by NIH support both of
individuals in training and of broader support of training programs at
undergraduate and postgraduate levels.

3. A start has been made toward assisting the schools in the
provision of programs of excellence by making it possible for them to
plan the selection of faculty and the recruitment of talented students

well in advance of the start of the academic year. By adjusting the starting

dates of training grant s so that commitments are made in June for the
ensuing fiscal year, the program itself is greatly improved and at the
same time the institution is strengthened. A total of $8 million of the
i960 training grant increase was used for this purpose , changing the
starting date on roughly one -third of the graduate training grants in
this field.

k. We continue to endorse the principle that granting agencies
should provide f or the full indirect costs (overhead) of r esearch that
is grant -supported . This is a primary concern both of grantee institutions
and of the Executive Branch. Practices now vary among Federal granting
agencies, but as a result of study, steps toward establishment of a
uniform indirect cost policy have been taken. In the meantime, since our
indirect cost practice is more restrictive than that of any other
Federal agency, it is again proposed that we lift the 15 percent restriction
that now obtains and permit payments up to an average of 25 percent,
starting with grants approved for payment after January 1, 1961.

5. The Administration has recently transmitted to the Congress
our legislative proposal to provid e research grants that are institutional
in nature instead of being defined in terms of a specific project. Under
this proposal, based on a formula which relates the size of the
institutional grant to the level of research activity of the institution,
up to 15 percent of the total funds available for NIH research grants
would eventually be apportioned among the institutions that contain

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these activities. This money would continue to be earmarked for
research, but its specific use would be discretionary with the
institution- -for establishing new research programs, adding research
resources, paying salaries, and hopefully establishing new career
opportunities for fulltime research personnel, and so on. This program
should not be interpreted to be one aimed primarily toward aiding
institutions. Rather, in meeting emerging research needs as they perceive
them, it would be a long forward step toward strengthening an
environment as a whole via grant support of its research function. It
stems from a strong conviction that a broadly based medical research
program for the Nation must continue to provide for peripheral decisions
of a substantive nature as a balance to those made centrally. It seems
quite likely, as an important indirect benefit, there would occur direct
strengthening of the institutions concerned. If the institutional research
grant legislation is enacted, we would propose to limit such support
initially to schools of medicine, dentistry, and public health, and to
start the program with 5 percent of the annual research grant appropriation.

6. A final aspect of current NIH activity bearing on institutional
strength and stability is found in the new grant programs for the devel-
opment of two kinds of research resources: therap eutic and metabolic
research c enters, a nd primate colonies . The Congress made available in
NIH i960 appropriations $3 million and $2 million respectively for these
purposes. They require different approaches from any programs in which

NIH has thus far engaged. In the clinical research units, we are support-
ing the development of specialized resources for controlled clinical
study within a single institution. The support includes renovation,
equipment, salaries, and operating costs. In the case of primate
colonies, we are asking selected institutions to develop for regional
use resources which will assure the ready availability of these
experimental animals for qualified institutions and investigators. The
regional nature of such resources has made it advisable to provide funds
for construction on a non-matching basis. The definitions and modus
operandi for both of these new programs have been worked out with extreme
care by NIH staff and outside advisors. The response of the medical
schools and universities has been gratifying, and a number of applications
from qualified institutions have been received and are under review by
the appropriate advisory bodies. The presence of these two programs in
our present activity warrants special comment because they represent
a new approach to the support of research—an approach that is directed to
general rather than specific progress in research, to institutional
stability, and to the development of resources to permit full use to
be made of the investigators' talents.

APPRAISALS OF NIH PROGRAMS
Inherent in the rapid growth and change of NIH programs is
the requirement they be both periodically and continuously appraised by
internal and external groups.

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The fundamental appraisal, of course, is that carried out
in the normal course of program execution. The nearly 700 nonfederal
scientists and leaders in public affairs who review and recommend
definitive action on our extramural programs, the distinguished
consultants who review our own research activities in Bethesda,
and indeed the many thousands of individuals receiving grants or
administering institutions in which grant -supported work is carried
out—these constitute a built-in appraisal mechanism providing a
continuous flow of knowledge as to the strengths and limitations of
our programs. In addition, the public interest and that of interested
groups, such as foundations, industry, and voluntary health agencies,
lead to assessments of performance from varied points of view.

From within the Federal establishment itself, there have been
a number of appraisals of special interest.

1. Under a resolution of the Senate Appropriations Committee,
a special group of advisors was called together to assess NIH's
current operations and to advise the Senate Committee as to their
probable trends and directions. These consultants, chaired by
Mr. Boisfeuillet Jones of Emory University, have spent a great deal
of time with the NIH staff and with others interested in our programs.
Their report will be made to the Senate this spring; for our part,
however, we have found it stimulating and helpful to have this kind of
opportunity to discuss and sometimes to defend what we do.

2. A second study of NIH extramural programs was completed
in November by the General Accounting Office as part of a larger study of all
NIH activities. Their report, transmitted to the Congress together with
my comments on their recommendations, contains four or five procedural
suggestions that will be helpful in maintaining better control over a
program whose rapid expansion makes these measures necessary and desirable.
Our staff has worked closely with the GAO subsequent to the preparation
of its recommendations. We believe that the study was conducted with
excellent insight into our operational policies and represents a
well-balanced appraisal of our activities. Its recommendations appear
sound. Several of these we had already initiated or determined for
ourselves to undertake prior to completion of their report, and adjustments
to meet the remainder are now in progress. We look upon this and all
other outside assessments of our activities as constructive and helpful,
and were grateful to the GAO auditors for pointing out ways to improve our
mechanisms for research support.

3- The Appropriations Committee of the House of Representatives
asked its staff to audit certain of the NIH programs and procedures. We
have not seen their report, but we found the views and line of question-
ing taken by this group to be very helpful and look forward to a
constructive report from the group.

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h. Although not directed to NIH programs specifically, studies
such as those carried out by the Office of the Surgeon General on the
supply of physicians and other health personnel, and on the increasing
significance of environmental hazards to the public health, were
valuable to us for program planning purposes.

5. Within our own establishment, a Task Force headed by

Dr. Kenneth M. Endicott made an intensive study of the impact of NIH
grant programs on twenty representative medical schools. The published
report, in which the Association of American Medical Colleges cooperated,
contained much of value both to us and to the schools. More recently,
Dr. Endicott has conducted a two-part study of NIH training programs.
The first part consisted of an assessment of the information that can
be gained from our own records, supplemented by a selective questionnaire
The second part was extended visits to selected schools to discuss and
evaluate their performance with training grant funds from NIH. There
has not yet been time for the results of this Study to be summarized
and evaluated; however, it is clear that it will be most helpful in
giving us additional insight into this rapidly growing segment of
our total program.

6. The need for improved information and surveillance as a
basis for informed administrative decisions has led to the establishment
within our Division of Research Grants of two units: one group to
maintain a continuous record of NIH support activities for the purpose

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of analysis and review , and a second group to provide in DRG the kind

of central activity for training grants that the Division now provides

for research grants. Such organizational arrangements are in the

process of being brought into balance by modifications of our administrative

structure within the Institutes and the immediate Office of the Director, NIK.

Steps are now being taken to provide senior staff assistance with special

competence to give leadership to present extramural programs and to

advise on emerging policies and problems in this field.

The above items are but a sample of the appraisal process as
applied to NIH programs. There are many other instances that could be
cited, at all levels. The essential point to convey is that in a support
role such as ours, where performance is geared in large measure to the
interests and capacities of others to do a job, the processes for
assessing each proposed step before actually defining and undertaking
it are of the utmost importance.

I960 PROGRAM PERFORMANCE
Perhaps the best background against which to measure NIH's i960
performance is found in the apportionment request submitted to and
approved by the Bureau of the Budget following the President's signature
of the Labor-HEW i960 appropriation act. The Budget provided funds and
indicated goals; the apportionment document outlined a philosophy of
operation and a plan of attack.

The bill contained increases of $115.8 million over the
1959 obligations for the nine appropriations administered by the NIH.
The bulk of this increase ($95 «6 million) was for grant -supported
activities; the balance was primarily for chemotherapy contracts
($6.9 million) and direct research activities ($5 million).

Our estimate at the time of the apportionment request was that
•I&.5 million might remain unexpended in research grant s, $1 million
in chemotherapy contracts, and lesser amounts in direct operations.
In retrospect, with the year more than half past, it appears to have been
a good estimate.

The i960 apportionment plan, including our $5. 9 million estimate
of unprogrammed reserve, was transmitted by the Department to the Bureau
of the Budget on August 26 and approved by the Bureau, as submitted,
on September 12, 1959 • The Bureau asked for a reappraisal by
December 1, 1959. Our response on November 25, 1959, essentially confirmed
the original apportionment estimates, although indicated the possibility
of slightly greater needs in some programs.

Among the substantive highlights of the NIH's i960 programs--
highlights which will be emphasized in the testimony of the Institute
Directors--I have selected ten for brief mention here.

1. The collaborative studies of perinatal disease by the
National Institute of Neurological Diseases and Blindness are now well
established, the cooperating institutions are moving ahead and preliminary

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data are beginning to flow from the participants. This long-term
undertaking, seeking new knowledge about mental retardation, cerebral
palsy, and other conditions, exemplifies the values NIH programs can
have when there is need for central planning, stimulation, and coordination
in a field of scientific endeavor, but also the difficult problems posed
by the need for central determination of plans and details of operation;
greater comprehension by the individual participants of their role in
the general plan; a great deal in the way of central supportive and
analytical services; and more broadly conceived informational functions.

2. The program of cancer chemotherapy, benefiting greatly from a
process of critical self-evaluation at this stage in its development,
continues to pursue the known paths and to seek new avenues that will
permit exhaustive exploration of the possibility that chemical agents
useful in the treatment of cancer may be found.

3. Another collaborative program is found in the National
Institute of Mental Health's studies in the field of psychopharmacology.

At a i960 level of more than $6.5 million, this program includes evaluation
of the clinical efficacy of drugs that are potentially useful in the
treatment of psychiatric conditions, the development and assessment of
ways to identify and characterize new drugs at the preclinical level, and
studies of the basic mechanism of action of known psycho-active drugs. In

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this program, too, the central functions of the Institute in support
of this essentially research grant activity are of great significance
to the continuing productivity of the program.

k. In the promising field of viruses and cancer a distinguished
group of virologists is now receiving sizeable, long-term support.
This is not a collaborative study in the sense that the perinatal
studies are. But the competence and relationships of these scientists,
and their informal agreement to explore different aspects of the field,
promises swift and imaginative exploration of the viral aspects of
cancer causation.

5. In part as a result of NIH interest, stimulation, and support,
considerable progress has been made toward the effective application

of the knowledge and techniques of mathematics and the physical sciences
to the solution of biological problems.

6. In the execution of its regulatory function, which for
biological products must be based on a solid research foundation,
the Division of Biologies Standards has given both leadership and
restraint to the development of a possible live virus vaccine against
poliomyelitis- -leadership to ensure that there is sound exploration
of all scientific aspects related to this experimental product, and
restraint so that all necessary assurances are obtained before it can
become available for general use.

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7. Progress on the four major structures at Bethesda now
being built to broaden NIH intramural programs continues to be
satisfactory. The new building to house the Division of Biologies
Standards is nearly complete and will be occupied this year. The
National Institute of Dental Research Building has its major structural
work completed. The addition to the surgical facilities of the
Clinical Center is progressing well. And the excavation has been made
for our badly-needed office facility. These four facilities, representing
a capital investment of some $18 million, will further establish NIH

as one of the Nation's major resources for health research.

8. As the substance and dimension of the NIH programs have
grown, there has been gradually increasing support for the research
of foreign nationals and for the interchange of scientists and
scientific information. These activities, for all Institutes,
reached a level of $8 million in i960, as contrasted with $5 million
in 1959« These "international" activities of NIH are in fact
National in objective and operation; the activities are supported to
carry out statutory missions, recognizing that attainment of the medical
research objectives of the U. S. requires cooperation with or support

of research in other countries and two-way exchange of scientists. In

this connection, it should be pointed out that NIH is itself becoming

an increasing focus for visits to this country by scientists from abroad.

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9« In the Division of General Medical Sciences, significant
progress has been made in the establishment of productive training
programs leading to the availability of greater numbers of people
trained in such basic disciplines as pharmacology, biochemistry,,
epidemiology, and genetics.

10, In the program of grants to assist in the construction of
health research facilities, now in its fourth year, the Council has
reviewed approximately $65 million in grant applications. The program
continues to meet an important need of the schools . The inability of
certain institutions to raise matching funds continues to be a matter
of concern.

Thus far in i960, Mr. Chairman, in the research grants field,
some 7;975 competing applications have been reviewed. This compares
with 5,833 in 1958 and 2,750 in 1956. During that four-year span,
however, the number of Study Sections has increased from 21 to 33 and
the average number of days per meeting from 1.8 to 2.6. Thus each
Study Section is reviewing only an average of 31 applications per
meeting day--fewer than six more than was true in 1956, and providing
one indication that it has been possible to maintain high review standards
during a period of rapid growth.

With the signing of the i960 Labor-HEW appropriation act, the
President developed a series of conditions to govern the expenditure
of NIH grant funds to help assure that certain potential hazards of rapid

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growth could be avoided. Such conditions, superimposed on normal
review procedures developed with excellence in mind, are difficult
of assessment in terras of their specific impact on programs. During i960,
a recent trend toward a decline in the approval rate on new grant
applications continued. Under special review procedures established
in compliance with the President's criteria, some 6k applications
approved with lowest priorities in June were denied support when
re-examined in October. At the same time, the volume of new grant
applications has continued to increase, and there has been no evident
decrease in the total volume of requests recommended for approval. An
examination of all of the objective evidence bearing on the qualitative
aspects of the research grants program suggests that it has been possible
to maintain high standards of review despite the rapid increase in
appropriations for the support of research.

The number of items that should be singled out for special
treatment in a general statement on NIH programs is almost without limit.
I have chosen to list a few program developments for sake of illustration.
We have prepared for the Congress, however, a detailed statement of the
research and program highlights related to NIH appropriations for 1959*
These will be introduced by the individual witnesses as they appear.
In sum, they constitute an impressive record of achievement toward the
goals set for medical research by the people who give it their support and
by the scientists and scientific institutions who foster and carry out
the research itself.

THE 1961 BUDGET REQUEST

The appropriation request for NIH contained in the President's
19ol budget request is -$^26.7 million. This compares with an estimated

operating level of $k2k.h million in i960 an estimated operating

level which is $5-9 million less than the i960 appropriation.

Included is a $5 million reduction below the authorized ceiling
of $j0 million under the Health Research Facilities Construction Act.
As indicated in earlier testimony of the Secretary of Health, Education,
and Welfare before this Committee, the Department is considering
legislation to make similar matching grants available for construction
of teaching facilities as well as research facilities in the medical and
related schools. If such legislation is enacted, the funds to be requested
would exceed the 05 million reduction in the Research Facilities
Construction program.

Also included is an increase in the availability of funds for
research, under a policy decision that within the ceiling authorized
an increase for this purpose should have priority over other aspects
of our total program.

Included in the consolidated appropriation request, "Buildings and
Facilities, Public Health Service," are three items seeking obligational
authority for NIH construction. An item of $1,150,000 is requested for
cage-washing equipment, cages, and alterations to our small animal
breeding facility, Wings F and G. This space has been in use for offices

- 22 -

pending completion of the new office building, and the funds are needed
to restore the space for its intended purpose. The other two items are
$350,000 to plan and construct an animal research facility needed at our
Drug Addiction Center at Lexington, Kentucky, and $250,000 for necessary
steps toward the development and use of the farm site acquired in
i960- -permanent animal buildings, temporary bleeding stalls, records
storage, and other minor structures, as well as completion of a master
site plan.

In sum, the budget request for I96I calls for a period of
consolidation of the gains achieved in i960, with a modest increase in
the support of research obtained through the implementation of decisions
indicated above.

As one looks ahead, it is apparent that the future evolution
of NIH programs will be shaped by forces such as these:

1. Greater attention will be paid to the development of research
resources and to mechanisms which will permit greater stability in
research careers.

2. Mechanisms for the support of current research will be
modified so that support of research in schools and other research
institutions will strengthen the institutions as such, as well as the
research function it contains, so that they can assume greater control
over their own destinies as well as their discrete research activities.

3. An increasing number of the decision-making processes which
determine the support of individual scientists in research and in
training for research will be decentralized to the local level.

h. Changes in the levels and mechanisms of support for medical
research will be accompanied by changes in scope and depth of penetration,
so that by using new techniques and embracing new disciplines, medical
research will be able to probe ever deeper into the unknown.

The dominant theme among those who study and report on the
present medical scene is the need for a broad and reliable financial
underpinning for the institutions of higher learning. Although research
programs can be designed to avoid placing further stress on the
institutions, they cannot meet their total needs. Ultimately, the present
schools must be materially strengthened and new schools created if the
Nation is to meet its obligations in a responsible fashion.

Some steps toward the achievement of these long-range goals are
reflected in the Administration's fiscal and legislative proposal for
196l : institutional research grants; initiation of increased overhead
on research grants; continuation of programs initiated in i960 to develop
research resources; continued broadening of NIH research grant programs;
and other activities designed to strengthen and return control to the
grantee institutions.

I am grateful to the Committee for its support and understanding
of the issues faced in this and former years during the development of
NIH programs. We will do our utmost in the administration of these
programs to demonstrate that your confidence is not misplaced.

ATTACHMENT A
DIVISION OF BIOLOGICS STANDARDS
BACKGROUND

The Federal Government's responsibility for the control of bio-
logical products began on July 1, 1902, with the passage by the Congress
of an Act to regulate the sale in interstate commerce of all viruses,
serums, toxins, and analogous products applicable to the prevention and
cure of diseases of man. The statute, now a part of the Public Health
Service Act, is basically the same as in 1902 when the technical respon-
sibilities of the biologies program were assigned to the National
Institutes of Health, then known as the Hygienic Laboratory. In 1937,
the Laboratory of Biologies Control was created within the National
Institutes of Health, and in 1948 it was made a part of the National
Microbiological Institute. In June 1955, authority was granted the
Surgeon General by the Secretary of the Department of Health, Education,
and Welfare to expand the biologies control function of the Public
Health Service to the status..of a separate division within the
National Institutes of Health, called the Division of Biologies
Standards. Its funds are derived from the appropriation "General
Research and Services, NIH", which also finances the Division of
General Medical Sciences.

GENERAL MISSION

The primary function of the Division of Biologies Standards is
to administer the provisions of the Public Health Service Act and
Regulations pertaining to the safety, purity, and potency of all

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biological products offered for sale, barter or exchange in interstate
commerce or for export or import. Such products include vaccines,
antitoxins, therapeutic serums, and human blood and its derivatives.

Biological materials are derived for the most part from patho-
genic or potentially pathogenic microorganisms. The preparation of
these materials requires careful control to minimize safety hazards
which might occur in the course of processing. In addition to safety
precautions, control measures are necessary to assure final products
of satisfactory potency. Effective control requires the design and
development of adequate and practical standards for production and
testing, careful surveillance of production methods, and the continuous
improvement of testing procedures.

The introduction in the early 1940' s of methods of producing
vaccines by growing the microorganisms in embryonated hens eggs
marked the beginning of rapid advances in the area of infectious
disease therapy. The first of these vaccines were typhus vaccine
and yellow fever vaccine. In 1955, a most significant change was
initiated with the production of poliomyelitis vaccine by tissue
culture techniques. These scientific advances have resulted in a
vast increase in the volume and types of such products with an
attendant major change of approach in industry to place greater
emphasis on research.

This makes it imperative for the Division to keep abreast of
the constantly developing advances by augmenting its research facili-

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- 3 -
ties and by the development of new lines of research within its
programs.
Control Activities

A system of licensing is the basis for the control of biological
products. This system involves the issuance of both establishment
licenses and product licenses, following the determination by the
Division that prescribed standards for safety, purity, and potency
have been met. These standards are set forth in regulations which
are continually reviewed for adequacy in the light of new advances.
Additional standards are formulated as new products are developed.

A total of 275 biological products are now licensed. These
are manufactured in 176 licensed establishments for which over 1,200
product licenses are in effect. A major activity of the control
program is the review of manufacturers' records of production and
testing and the testing in the Division's laboratories of representative
samples of these products. Tests, ranging from relatively simple
sterility tests to complex, time consuming, costly potency deter-
minations are carried out each year on over 3,000 individual lots of
a wide variety of biological products.

In addition to the inspection of manufacturing facilities and
procedures prior to licensing, each licensed establishment is inspected
annually to assure continuing compliance with prescribed standards.
Close liaison is maintained with representatives of professional and

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- 4 -

technical staffs regarding proposed plans for new facilities and for
modification of existing structures and equipment insofar as they
affect the safety, purity, and potency of biological products.

To assure that each licensed product is consistently acceptable
and of uniform potency, standard physical reference preparations are
developed and distributed to manufacturers and laboratories engaged
in the standardization of biological products. Approximately 4,000
vials are distributed annually by the Division.

The control of biological products has been characterized from
its beginning by the close cooperation between the Division and the
manufacturers. Frequent meetings are held between members of the
Division's professional and administrative staffs and groups of
manufacturers who have common problems. In addition, from 150 to
200 conferences are held each year with technical representatives
of manufacturers to discuss production and testing problems peculiar
to their own organization. Through such cooperation with the technical
representatives of industry, as well as with independent investigators
throughout the Nation, the Division frequently identifies potential
problem areas in biologies production and control before serious
difficulties arise. Division scientists, serving as members of
international study groups, continue to take an active part in the
World Health Organization's program for the development of international
uniformity of biological products. Coordinated with the proposed

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World Health Organization's cooperative effort to establish an inter-
national laboratory standard of potency for cholera vaccine, DBS
scientists are investigating improved methods for evaluation of the
potency of cholera vaccine. It is only when such comparative data
are available both in field and in laboratory studies that a standard
of potency reflecting protective activity in human beings can be
established. Major emphasis in this study is placed on standardization
of technical details related to the performance of quantitative potency
tests.
Research Activities

The control program of DBS is necessarily supported by an
active research program, enabling the Division to keep abreast of the
development of new and improved immunizing agents, and to prepare
physical references as well as testing procedures for these products
once they are ready for commercial production.

This year considerable effort has been devoted to problems
related to live poliovirus vaccine. While continuing a control and
research program on killed poliomyelitis vaccine, extensive laboratory
investigations have been carried out by the Division in an attempt to
characterize, on a quantitative laboratory basis, the live poliovirus
strains being used in field trials in this country and abroad. The
fact that three separate sets of strains have been prepared multiplies
the complexity of the problem. A continuing review of progress in

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this area is made by the PHS Committee on Live Poliovirus Vaccine.
Data, as they become available from these field trials, are subjected
to evaluation with reference to the safety and effectiveness of the
vaccine. Development of recommendations relating to the production
and testing of live poliovirus vaccines has also continued.

Changes designed to improve the killed poliomyelitis vaccine
continued to be introduced. The Division utilizes the assistance of
the Technical Committee on Poliomyelitis Vaccine to maintain close
cooperation with the technical representatives of industry, giving
attention to problem areas, both actual and potential.

The desire of the medical profession for products which will
immunize against several diseases simultaneously has been partially
fulfilled during the year by the introduction of two multiple antigen
products: 1) Poliomyelitis vaccine has been combined with diphtheria
tetanus, and pertussis immunizing agents for use in pediatrics, thus
providing a convenient means of broad immunization against four major
diseases, 2) The combination of influenza viruses and the adenoviruses
offers the advantage of protection against members of two classes of
respiratory agents with a single course of inoculation. The anticipated
field of usefullness for this combined antigen as demonstrated in field
trials, is the reduction of acute upper respiratory infections in
susceptible age groups such as military recruit populations.

The preparation of multiple antigens is a complex process. The
compatibility of the components and their stability in combination can

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be determined only after searching study, followed by thorough clinical
trials to determine their effectiveness. The Division has worked
closely with industry and other research groups on these problems as
well as the development of testing procedures and the modification
of required standards essential for control of such products.

Although progress in the development of a commercial measles
vaccine has been slow, studies relating to the eventual preparation
of a standard reference reagent, as well as standardization tech-
niques appropriate for effective evaluation of such an immunizing
agent, continue. Collaborative work is also being carried out with
other research laboratories in the development and testing of experi-
mental measles vaccines. Work on the standardization of gamma globulin
for measles antibody content is also being pursued so that it can be
used more effectively in the control of measles epidemics.

The long-term study on the effects of storage conditions on
albumin are being continued in order to determine the nature of the
changes observed in liquid albumin stored at room temperature. Data
observed during these studies reveal the need for refrigerated storage
of such products. Technical data which has also been provided permit
an extension of the dating period for one such product.

As a result of studies on long-term preservation of red blood
cells by freezing which demonstrated the possibility of using such
cells successfully even after storage for a number of years, it has

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- 8 -
been possible to establish a special repository of extremely rare
bloods for emergency use. The Division has recently stored 20 rare
bloods by this method and the project is being expanded as additional
rare donors become available.

It is anticipated that the Division's program for 1961 will
follow the same lines as it has taken during the past two years. A
flexibility will be maintained which will permit direction of emphasis
according to the needs arising from the development of new and improved
biological products. An additional coordinating influence will be the
occupancy of the new building which will occur during 1961.

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SUMMARY OF OPENING STATEMENT
by
Assistant to the Director for International Affairs,
National Institutes of Health

COMMITTEE ON APPROPRIATIONS
1961 ESTIMATE
for
Scientific Activities Overseas (Special Foreign Currency Program)'

Mr, Chairman and Members of the Committee:

The objective of this program is the support of medical
research in other countries through use of foreign currencies
available under the terms of Section 104(k) of Public Law 430. A
total appropriation authorization of $3,707,000 is being requested
for this purpose. The research efforts to be supported with these
funds will be directed toward the solution of disease and health
problems which are of particular importance in the respective countries,
but which also hold promise of contributing knowledge of value and
significance to the advancement of medical research in the United
States and the world generally. These research activities also will
make possible the training of many younger scientists whose
professional growth will add to the medical research resources of the
world and the potential for greater progress in the future as well as
provide additional areas of training for the scientists of the United
States.

The activities proposed for support through use of P.L. 400 funds
have been developed from suggestions and proposals made by scientists
and research investigators in the various categorical programs of the

- 2 -
National Institutes of Health. They represent an appraisal of
research problems of major importance in those countries where
significant balances of P.L. 430 funds exist. The final determination
of the specific research activity that will be carried out will be
dependent upon such factors as the number of qualified investigators,
the character of existing facilities, and the development of
appropriate collaborating arrangements with research institutions
and authorities in the respective countries. When these factors have
been fully ascertained, it may be necessary to shift the character,
emphasis or type of these research activities from those upon which
this summary estimate has been based.

Specifically, the funds requested would support such coordinated
activities as: (1) cholera research in India and Pakistan; (2) schisto-
somiasis research in Brazil and Egypt; (3) studies of tropical
diseases such as filariasis, toxoplasmosis, amebiasis in countries
as India, Pakistan, Indonesia, Israel, and Brazil; (4) regional
laboratories for virus research in Asia (India), the Middle East
(Israel), Southern Europe (Yugoslavia), and Northern Europe (Poland);
(5) comparative cardiovascular diseases research in India and
Yugoslavia; (6) nutrition studies such as kwashiorkor in India and
pellagra in Yugoslavia; and (7) cancer epidemiology studies.

It is anticipated that projects to be developed with these
funds would be handled either as grants or contracts, following

- 3

procedures normally applied in the National Institutes of Health's
program. Other appropriate means of securing technical advice will
be used, particularly the opinions of competent scientists and
scientific bodies within the countries concerned. However, no
project will be supported contrary to the wishes of the official or
semi-official governmental body which is responsible for the over-all
planning and coordination of research efforts in each country. The
funds will be used only to support additive research and will not be
used to substitute for the support which each country would normally
put into such research efforts, or which would normally be eligible
for support from dollar appropriations. Since the funds will be
available until expended, each project, when approved, will have
:unds allocated for the necessacy duration of the project, up to five
years, as a means of insuring stable support.

OPENING STATEMENT
by
Assistant L o the Director, National Institutes of Health,
for International Affairs

COMMITTEE ON APPROPRIATIONS
1961 ESTIMATES
for
'•Scientific Activities Overseas (Special Foreign Currency Program)

Mr. Chairman and Members of the Committee:

It is a pleasure to appear before you today on the behalf of
this program, which has as its objective the support of medical
research in several countries through use of foreign currencies
available under the terms of Section 104(k) of Public Lav; 400. A total
appropriation authorization of $3,707,000 is being requested for this
purpose. The research efforts to be supported with these cunds will
be directed toward the solution of disease and health problems which
are of particular importance in the respective countries; in some
instances this provides conditions and situations that are not
available in the United States, but are important to study for their
relevance to our problems. Thus, the program holds promise of.
contributing knowledge of value and significance to the advancement of
medical research in the United States and the world generally. The
expanded research activities which will be made possible through the
use of these funds will enable progress in the control and eradication
Ol major disease and health problems and in the basic understanding of
disease and disease processes. It will also make possible the training
of many younger scientists in these countries whose professional

- 2 -
growth will add to the medical resources of the world and the potential
for greater progress in the future, as well as provide additional areas
of training for the scientists of the United States.

I think it important, at the outset, to point out that the
activities posed in this request represent the first venture of the
National Institutes of Health in the support of research in foreign
countries through the use of P.L. 480 funds. In 1950 the National
Institutes of Health, in conjunction with other Federal agencies,
requested the appropriation of $175,000 for the purchase of P.L. 430
currencies to support four projects involving the translation of
Russian and other literature and periodicals in the medical sciences.
These funds were appropriated in the First Supplemental Appropriation
Act of 1959, and in accordance with the direction of the President are
being administered through the Science Information Service of the
National Science Foundation (NSF). This program is now well under way.

The authorization which is being requested this year, however,
will be utilized for the conduct of medical research activities, The
National Institutes of Health, under its regular operating
appropriations, supports research in foreign countries through research
grants, resulting from applications submitted by foreign scientists
and investigators interested in securing U. S. support for their
ideas. The approval of these grants, however, is made under a policy
which limits support to those research projects which involve

- 3 -

activities of a character or quality which is not available to the
U. S. The amount of National Institutes of Health support for research
in foreign countries is therefore quite small at the present time,
amounting to about $2,9 million in 1960.

The activities proposed for support through use of P.L. 480
funds have been developed from suggestions and proposals made by
scientists and research investigators in the various categorical
programs of the National Institutes of Health. They represent an
appraisal of research problems of major importance in those countries
where significant balances of P.L. 480 funds exist. We believe the
investigation of these problems will contribute valuable knowledge
to medical research in the U. S. and the world in genesal as well as
be of benefit to the countries involved. We are also confident that
the research personnel and facilities necessary for this work are
available in the respective countries. We have not had the opportunity
to make a final on- the-ground assessment of either problems or
resources, nor the opportunity to discuss in detail with our scientific
colleagues in these countries the details of many of the specific
projects. The estimate submitted here, therefore represents our best
judgement concerning the nature of the research which might be
undertaken and the funds which will be required for its support.

The final determination of the specific research activity that
will be carried out in the several countries involved will be dependent

- 4 -
upcn such factors as the number of qualified investigators, the
character of existing facilities, and the development of appropriate
collaborating arrangements with research institutions and authorities
in the respective countries. When these factors have been fully
ascertained, it may be necessary to shift the character, emphasis or
type of these research activities from those upon which this summary
estimate has been based. This will be necessary in order to take
maximum advantage of the research opportunities and resources
available in the several countries. In selecting specific research
projects to be carried out, effort will be made to choose those
activities which may yield information of value to both the problems
of local concern and to questions of interest to the United States.
Many research projects will be linked with others in similar
or dissimilar geographical regions against targets of common concern,
e.g. virus diseases and atherosclerosis. Comparative investigations
using epidemiological techniques will study areas where the incidences
of diseases such as cancer, heart diseases, dental caries, and mental
ailments ace either abnormally high or low.

MECHANISMS FOR THE DEVELOPMENT OF RESEARCH PROJECTS
It is anticipated that projects to be developed with these funds
would be handled either as grants or contracts, following procedures
normally applied in the National Institutes of Health's program. This
means that all projects would be subjected to technical scrutiny and

- 5 -
evaluation by a "jury of peers 1 '' such as is available through the
National Institutes of Health Study Sections. Other appropriate
means of securing technical advice will also be utilized, particularly
the opinions of competent scientists and scientific bodies within the
countries concerned. No project will be supported contrary to the
wishes of the official or semi-official governmental body which is
responsible for the over-all planning and coordination of research
efforts in each country. Cn the contrary, such groups will be used
to the maximum possible extent in assisting in the design and
organization of projects within their country.

The funds will be used only to support additive research and
will not be used to substitute for the support x^hich each country
would normally put into such research efforts. Likewise these funds
will not be used to support projects which would normally be eligible
for support from dollar appropriations. Since the funds will be
available until expended, each project, when approved, will have funds
allocated for the necessary duration of the project, up to five years,
as a means of insuring stable support.

TYPES OF PROJECTS

The following are examples to illustrate the disease problems
and the research opportunities which may be realized through this
program.

- 6 -

1. Choi era - -Choi era represents one of the few major bacterial
epidemic diseases whose control has not yet yielded to modern scientific
approaches. Experts in the field believe that a properly designed and
supported research effort would produce the knowledge necessary to
bring the disease under control. The funds requested herewith would
support coordinated research activities in India and Pakistan. The
projects would be a part of a total attack on cholera which would also
include research activities in other countries,

2. Schistosomiasis - -There is substantial evidence that this
disease is of growing importance since the rapid development of
irrigation schemes is providing new sources for the spread of the
infectious agent and for the propagation of the snails which act as
the intermediate host.

The funds requested would be used to organize coordinated
projects in Brazil (field trials of therapeutic and prophylactic agents),
and in Egypt (systematic study of the epidemiology of the disease and
of che intermediate hosts). These projects would also be organized to
permit the study of cases particularly from the viewpoint of inter-
relations between diet and the disease as well as certain clinical
features of the disease, now imperfectly understood, such as liver
cirrhosis and portal hypertension.

3. Other Tropical Diseases —Studies of certain aspects of other
important tropical diseases such as filariasis, toxoplasmosis, amebiasis,

- 7 -
kala-azar, Chagas ' disease, and malaria are planned. The studies to be
undertaken would vary with the disease but would include testing of
therapeutic agents, better diagnostic methods and evaluation and study
of certain poorly understood features of the clinical disease. These
studies would be possible in India, Pakistan, Indonesia, Israel, Poland,
Yugoslavia, and Brazil.

4. Virus Diseases --The influenza pandemic of 1950 demonstrated
once again the global spread of a viral agent, and the benefits that
are derived from adequate arrangements to observe its occurrence and
distribution, its means and routes of spread. The World Health
Organization and many national organizations and experts are unanimous
in their conclusion that a world-wide network of regional laboratories
is needed to acquire knowledge for the great variety of viral agents.
The funds requested herewith would be used to provide basic support
for such regional research laboratories in Asia (India), the Middle
East (Israel), Southern Europe (Yugoslavia), and Northern Europe
(Poland) .

5. Cardiovascular Pis eases --Increasing evidence is accumulating
that suggests that the type and amount of dietary fat is a major
factor contributing to the incidence and severity of atherosclerosis
and the diseases associated with it, such as coronary artery disease
and cerebrovascular accidents. Two countries, India and Yugoslavia,
contain population groups who use dietary fats almost exclusively of

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- 8 -
one type. Closely adjacent populations are available which use
completely different types and amounts of fat. Yet these populations
are otherwise similar as to genetics, physical environment, and
socio-economic factors. This would be an excellent opportunity to
gain further knowledge of widespread significance through properly
designed epidemiological and ecological studies.

6. Nutrition --To understand further the nature of nutritional
deficiencies, and to understand better the function of the essential
nutrients in basic life processes it is essential to study individuals
suffering with nutritional diseases. Numerous specific examples of
unusual research interest and opportunity can be cited, such as
blindness from Vitamin A deficiency in Indonesia and India, kwashiorkor
in India and many other countries, the unique naturally occuring
deficiency of the B vitamin pantothenic acid in India, and pellagra in
Yugoslavia.

7. Cancer - -The opportunities to acquire further knowledge
concerning environmental factors which may be related to the incidence
of various forms of cancer exist in countries where P.L. 430 funds are
available. Of particular interest are studies on the relationship of
schistosomiasis and bladder cancer in Egypt, of protein deficiency

and liver cancer in Indonesia, and of nutritional deficiencies and
intraoral cancer in India.

SUMMARY OF OPENING STATEMENT
by
Chief, Division of General Medical Sciences,
National Institutes of Health

COMMITTEE ON APPROPRIATIONS
1961 ESTIMATE
for
"General Research and Services, Public Health Service"

Mr. Chairman and Members of the Committee:

This statement is on behalf of the Division of General Medical
Sciences which receives its funds from the research and training
grants portion of the General Research and Services Appropriation.

This Division administers the grant programs of the National
Institutes of Health for research in the sciences basic to medicine
and biology, in environmental and public health, and in certain clin-
ical sciences not covered by the programs of the Institutes. In
addition, the Division administers the grant programs for training
investigators in the basic biomedical sciences, provides fellowships
for general research training and directs the NIH Center for Aging
Research.

The research responsibilities of the Division fall into six
principal areas. The first two, Chem istry of Life Processes and
Human Development , cover fundamental research in a number of areas
crucial to medical progress. In recognition of the growing emphasis
on, and need for, basic research, about half of the Division's total
research funds go Into these categories. The other four categories

- 2 -
are Environmental Health , Public Health , the Clinical and Preclinical
Sciences , and Methods and Tools of Science . In all six areas I am
happy to report that during the past year the Division has taken
major strides forward in promoting significant scientific achieve-
ment.

As greater emphasis has been placed on the national medical
research effort, needs have continued to increase for the trained
manpower to conduct this research, and to teach, in the basic sciences.
In the Division's research training program, grants are made to re-
search institutions to help increase the number of highly trained
scientists undertaking investigative careers in ten major areas of
academic medicine and public health: Anatomical Sciences, Bio-
chemistry, Biometry, Embryology and Development, Epidemiology,
Genetics, Pathology, Pharmacology, Physiology and Microbiology, In
a related activity, the Experimental Training Grants program helps
the medical schools develop new approaches to the training of medical
students for research careers. To provide additional flexibility in
the training program of the Division, research fellowship awards are
made to individual scientists at various stages of their training in
research.

In the field of aging, the NIH Center for Aging Research has
actively continued its assignment of stimulating and coordinating
research and training in gerontology, both through grants to non-
Federal institutions and through direct research by all of the

--.-:■ t -
. .... *

- 3 -
Institutes of NIH. The total NIH support of extramural projects re-
lated primarily to aging was over $2 2 000,000 in 1958; $4,133,980
in 1959; and approximately $8,600,000 at present. The number of
individual extramural projects has increased from 131 to approxi-
mately 273. Projects secondarily related to aging today total 374
and amount to approximately $5,800,000 a year. These figures indi-
cate substantive progress in answering many questions about aging,
but much more work needs to be done, and we are continuing our ef-
forts to stimulate research in this field.

In conclusion, Mr„ Chairman, the appropriation request for the
Division of General Medical Sciences for 1961 is a total of
$44,638,000 as compared with the appropriation of $43,189,000 for
I960. This allowance for 1961 will provide for the continuation
of 1960 program levels in all activities and will permit some increase
in grants for research projects. This request for 1961 is distrib-
uted among program activities as follows:

Research projects........ $26,446,000

Research fellowships 5,310,000

Training . . . c 11 ,540,000

Review and approval of grants ...... 1, 34?. ,000

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OPENING STATEMENT
by
Chief, Division of General Medical Sciences,
National Institutes of Health

COMMITTEE ON APPROPRIATIONS
1961 ESTIMATE
for
"General Research and Services, Public Health Service"

Mr. Chairman and Members of the Cotrmittee:

My statement is on behalf of the Division of General Medical
Sciences, which receives its funds under the research and training
grants portion of the General Research and Services Appropriation.
The other division supported by this appropriation, the Division of
Biologies Standards, has been discussed by the Director of the National
Institutes of Health in his opening statement.

The Division of General Medical Sciences administers the grant
programs of the National Institutes of Health for research in the
sciences basic to medicine and biology, in environmental and public
health, and in certain clinical sciences not covered by the programs
of the Institutes. In addition, the Division administers the grant
programs for training investigators in the basic biomedical sciences,
provides fellowships for general research training and directs the NIH
Center for Aging Research.

The research and training programs were established, and have
grown at an appreciable rate, as the result of needs, particularly in
certain basic science areas, which could not be adequately met by the
disease-oriented, categorical programs of the Institutes.

- 2 -

In recent years there have been remarkable achievements in
learning more about the fundamental physiological and biochemical
processes of man and more about the nature of life itself. New dis-
ease conditions have been defined and new drugs and other new forms
of therapy have been developed -- fundamental steps which are crucial
to the advancement of medicine. These new biological and medical
accomplishments have served at the same time to reveal previously un-
explored areas which the scientists now must study.

Concurrently, there has been a commensurate growth in the need
for training more researchers in the basic biomedical sciences. It
is quite plain that we should seek to improve both the quantity and
quality of research manpower if the level of research itself is to be
adequate.

These needs for increases in both basic biomedical research
and basic research training were recognized by the National Institutes
of Health in the establishment of programs in the Division of Research
Grants. From fiscal years 1956 to 1959 these programs grew from a
level of $5,000,000 to $26,721,659. They were transferred to the
Division of General Medical Sciences when it was established in July
1958. For fiscal year 1960 a budget of $43,189,000 was provided to
cover our responsibilities for basic research and for research in en-
vironmental and public health and in certain applied medical sciences.

Along with these other organizational moves, the Center for
Aging Research, which serves as a focal point for all NIH grant

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activities in aging, was transferred from the National Heart
Institute to become a component of the Division of General Medical
Sciences.

My remarks today, therefore, will be concerned with these three
areas of the Division's program: research, research training and aging,

RESEARCH

In the 18 months since the Division was formed, and particu-
larly in the past year, our research responsibilities have been
organized into six principal areas. I am happy to report that the
Division has taken major strides forward in promoting scientific
achievement in each of these six areas.

First are the two important basic research fields which consti-
tute the foundation of most other biological and medical areas:

(1) THE CHEMISTRY OF LIFE PROCESSES. There are few problems
in all of science more exciting than the study of the nature of life
itself: how non-living chemical substances such as amino acids are
joined together to form the protein of all living matter; under-
standing how enzymes act to facilitate chemical reactions in the
body; how pharmacologic drugs act on man; and how genes -- the all-
important carriers of heredity — are formed. These are all questions
to which the Division grantees are addressing themselves. About
one-fourth of our research grant funds are devoted to this area.

(2) HUMAN DEVELOPMENT. The biology of human development is
the second major concern of DGMS. Here our attention is devoted to

- 4 -
the development of the organism from conception through embryological
stages to birth and on through childhood and adulthood to old age.
The sciences of genetics, embryology, cell biology and physiology are
paramount here. This area comprises about one-fourth of our grant
program. About half of our funds, therefore, are going into basic re-
search areas.

Next, let me mention two broad fields of study relating the
individual to his environment:

(3) ENVIRONMENTAL HEALTH is currently receiving well-deserved
attention from scientists and from the public. The dangers to health
stemming from our environment are frequently not so dramatic or dis-
cernable as the effects of cancer or heart disease, but they possess
the insidious characteristic of being always with each and every one
of us, in the water we drink, in the air we breathe, in the food we
eat, and in the lurking hazards to which man exposes himself in his
work, travel and play. Research on these topics comprises one- fifth
of the DGMS program.

(4) PUBLIC HEALTH. The health resources to which a doctor or
patient can turn when illness occurs are a major focus of public
health today. Research is needed on the prevalence and epidemiolog-
ical characteristics of disease; what kind of medical services are
most effective, most needed, or most economical; and what forms of
rehabilitation and nursing are most satisfactory in returning a pa-
tient to productive life.

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In addition, the Division provides grant support for two areas
of medical science; the substance of which crosses categorical dis-
ease lines:

(5) THE CLINICAL AND PRE-CLINICAL SCIENCES supported by EGMS
include anatomy, endocrinology, general surgery, anaesthesiology,
orthopedics, pediatrics, and others.

(6) METHODS AND TOOLS OF SCIENCE, Through this program NIH
promotes research on improving the techniques and tools of scientific
achievement: the development of new methods for biological measure-
ment and of new instrumentation, studies of how to make the medical
literature more readily available and useful to scientists, support
of certain specialized meetings of scientists to speed up the ex-
change of research findings and problems, and the preparation of
specialized biological handbook materials.

Slightly less than a third of our funds go into these latter
three areas.

During the past three years, the Congress has recognized the
importance of these six areas by making progressively larger appro-
priations for research grants. The appropriation for fiscal year
1958 was $9,468,000; for 1959, $16,621,000; and for 1960, $23,559,000,
These funds have permitted the support of 645 research projects in
1958, 1,065 in 1959, and an estimated 1,470 in 1960. The distrib-
ution of these grants by area of interest during the present fiscal
year is shown in the following table:

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Estimated Number Estimated
Field of Research of Research Projects Cost

FY 1960 FY 196

Chemistry of Life Processes 415 $5,561,000

Human Development 534 6,110,000

Environmental Health 255 4,704,000

Public Health 92 3,728,000

Clinical & Pre-Clinical Sciences 97 1,682,000

Methods and Tools of Science 77 1.774,000

1,470 23,559,000

The increase in research grant funds available to us during

fiscal year 1960 has permitted orderly expansion of the support of

high quality research. The review of applications by Study Sections

and by the National Advisory Health Council has remained as rigorous

as in the past, and with the application of the President's Criteria

has possibly been even more rigorous in borderline cases. The large

increase in expenditures, therefore, is simply a reflection of the

fact that many more applications of high quality were received than

in preceding years.

Of our total expenditures for research grants this year,

$647,611, or three percent of our funds, is going to support research

projects outside the United States. This involves 37 grants.

During the coming year the Division plans to devote special

attention to the support of grants in certain areas of particular

scientific or public concern. These include:

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- 7 -

1) studies of the effectiveness and availability of medical
care and services, especially for the aged,

2) biomedical engineering, the adaptation of tools and concepts
from the engineering sciences for use in medicine and biology,

3) the stimulation of much needed studies of comparative anat-
omy, in order that we may more effectively and speedily utilize the
findings of animal research in the control and prevention of human
disease,

4) the effects of toxic agents on man, whether these originate
as air pollutants, water pollutants, food contaminants, or industrial
materials.

Beyond these, special note should be made of the increasing
frequency with which NIH staff are consulted with respect to the
establishment of major research centers in which a variety of scien-
tists may bring their various skills and knowledge to bear on a
single topic or problem. The Division of General Medical Sciences
has been charged with the responsibility of administering grants to
establish a limited number of clinical research centers. It also
currently provides support, or has proposals under review for support,
of research centers of regional or national importance in the field
of aging, genetics, cell biology, and biomedical engineering. It is
hoped that these new activities will provide a sound pattern for the
development of regional research resources of many kinds.

With regard to accomplishments in specific areas of research

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in the past year, I understand that the document "Highlights of Prog-
gress of Research in General Medical and Biological Sciences" will be
presented as in past years, but I think that at this point the Com-
mittee might be interested in a' very few selected examples of the
type of work the Division is supporting.

In the basic research areas, one scientist has produced some
remarkable results in his experiments with proteins, a fundamental
component of living matter. In earlier work this scientist reported
making a primitive protein from combinations of 18 amino acids.
More recently he has reported a successful effort to convert the
proteinoids into spherules which closely resemble cells. The work
may be of tremendous significance in understanding how life was
first formed on the earth and how primitive proteins became living
cells.

A work significant in diagnosing kidney disorders has been re-
ported by a scientist studying renal aminoaciduria. He has found a
practical method, using paper chromatography, for analyzing amino
acid concentrations in a urine sample, and has reported that patterns
of the different concentrations help to indicate the presence and
nature of certain diseases.

Another scientist has made some noteworthy advancements in
studies of the effects of extreme cold on animals and human beings.
He reported the successful reanimation of mice cooled to less than
32 degrees (Fahrenheit) and progress in determining the most effective
techniques for resuscitation by using heat and combinations of air,

- 9 -
oxygen or mixtures of oxygen and carbon dioxide. The work has im-
portance in aiding the revival of persons suffering from extreme
cold. It also has considerable significance with respect to the in-
duction of low body temperatures as a therapeutic measure.

In the field of food technology, one scientist has been study-
ing the results of combinations of certain insecticides on foods. He
has used approved insecticides, experimenting with what could happen
if, for example, a person ate one insecticide from an apple and an-
other insecticide from some grapes. In three out of 15 combinations
he found that the toxicity was potentiated greatly, enough in fact
to kill the test animals. The work obviously points to the need for
much more research in this area.

Other work includes the finding that wounds, closed immedi-
ately after exposure to certain low levels of irradiation, will heal
normally; that axillary granuloma can be caused by the metal zirco-
nium as a constituent of anti-perspirant preparations; that the
fetal electrocardiogram is quite effective in diagnosing multiple
pregnancies. We also have contributed to medical technology in the
development of methods for measuring the motility of the esophagus;
a new method of bronchography; two instruments for measuring and
analyzing acids and aerosols in the air; and a new, small instrument
which can be attached to a patient's chest to measure his heart
activity for periods up to 24 hours.

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Funds totaling $26,446,000 are being requested for research
grants during 1961, an increase of $2,887,000 or about 12 percent
over last year.

TRAINING

As greater emphasis has been placed behind the research effort,
shortages have continued to mount in trained manpower to conduct this
research, and to teach, in the basic health-related sciences.

There are several aspects to the overall problem:

(1) The general need for investigators and teachers in the
basic sciences exceeds the supply.

(2) Investigations in the clinical fields not only are depend-
ing more heavily than ever on advances in the basic sciences, but are
continuing to draw personnel from the basic areas, commonly because
of the attraction of higher salaries,

(3) Young physician- investigators, recognizing needs for basic
science training, have put greater demand on university and pre-
clinical science departments for appropriate opportunities.

(4) Medical educators are calling for an expanded medical
teaching program if the nation's supply of physicians is to remain
adequate for the health needs of the nation's expanding population.

The evolving nature of modern medical and biological research
and teaching, therefore, has added significantly to the already grave
obligations of the teachers and scientists in the basic fields, which
themselves have suffered a lack of adequate attention and support in
the past.

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The importance of meeting these needs is emphasized by the fact
that it takes between five and ten years to prepare a scientist for a
productive career; so that training programs undertaken now are
planned to try to meet conditions in 1965 or 1970 when the require-
ments will be even more critical than at present.

The needs to support the training of research scientists have
long been recognized by the National Institutes of Health with train-
ing programs in specific fields, such as psychiatry, neurology,
rheumatology and cardiovascular diseases. Several years ago, as we
mentioned earlier, NIH launched its programs to help support the
training of investigators in the fundamental sciences. The Division
of General Medical Sciences became the principal NIH unit for these
research training and fellowship programs when it was established in
July 1958.

The programs have the following goals: (1) To strengthen the
research training institutions and increase their potential for devel-
oping teachers and scientists; (2) To aid the flow of competent,
highly-motivated students through the graduate schools of the univer-
sities; (3) To expand the opportunities for intensive training of
predoctoral and postdoctoral candidates in additional research insti-
tutions wherever appropriate; and (4) To encourage and support the
greater utilization of trained manpower to improve the teaching and
training functions of the universities and research institutions.

I will discuss first the training grant program including the

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- 12 -
Experimental Training Grants Program, and then fellowships, with
special emphasis on the Senior Research Fellowship program.

Research Training -- This program provides grant funds to
public and private nonprofit institutions, such as the medical schools,
for the establishment, or improvement of graduate research training.
The purpose is to increase the number of highly- trained scientists to
undertake investigative careers in academic medicine and public health.

Although projects may be supported in any basic biomedical or
health-related science where scientific manpower shortages exist,
regular programs in ten areas are being operated by Division of Gen-
eral Medical Sciences at present. Two of these of long-standing
importance, Epidemiology and Biometry, were in existence at NIH for
some years before being assigned to Division of General Medical
Sciences. During 1959, we established seven more, in the Anatomical
Sciences, Biochemistry, Embryology and Development, Genetics, Path-
ology, Pharmacology, and Physiology, and we currently are establishing
a program in Microbiology. Each program functions under the guidance
of Training Committees composed of non-Federal scientists and other
experts in those particular research and training fields.

At present (February) these programs are supporting a total
of more than 286 research training activities in universities and
other institutions across the nation.

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- 13 -
The following figures will give an idea of the growth of the
work in recent years:
Year Appro p riation Nu mber of Training Projects Supported

1958 $2,962,000 75

1959 6,040,000 163

1960 13,040,000 315

By the end of fiscal year 1960 there will be an estimated total
of more than 1,700 graduate and postdoctoral students in a research
training status. Already these awards have had a marked effect in
helping provide stability to the basic science departments of many
schools, by allowing an increase of postdoctorate training opportun-
ities, and by improving the quality of the end product -- the trainee.

The very existence, of these training awards has led to other
and somewhat unexpected dividends. There are indications that the
availability of funds has stimulated additional numbers of students
into serious consideration of research and academic careers. Also,
the improvement of facilities and faculty interest for graduate train-
ing indirectly has effected marked improvements in undergraduate
teaching; and the prestige attached to the receipt of one of these
highly competitive awards has stimulated departments to increase their
efforts in obtaining and selecting high caliber trainees.

The training program, then, has already met its initial aims;

(1) There has been an increase in the total number of depart-
ments, capable of turning out well-trained scientists;

(2) The quality of all training programs has been markedly im-
proved ; and

- 14 -

(3) There has been a significant increase in the number of com-
petent trainees who have recently completed or are completing their
postdoctoral research training and are thus available for academic
careers at junior or intermediate staff levels. In particular, the
appearance of well-trained basic scientists in certain shortage fields
has increased the demand for such scientists through the demonstra-
tion of their effectiveness in contributing to new areas of research.

Research training in many of the basic and health-related
sciences is in a continual state of transition, which flows from the
recent and significant advances in related areas of research, in
instrumental techniques and in experimental design. Our training
grants have allowed the placing of special emphasis on certain of the
key or critical areas, where timing is important, by providing the
needed support and impetus for the growth of these fields as research
sciences.

For fiscal year 1961, funds in the amount of $11,040,000 are
requested for the research training program.

Experimental Training Grants Program -- This program, initiated
in 1957, has enabled 13 medical schools to carry out experimental
efforts aimed toward the improved development of medical scientists
and teachers. More specifically, the funds enabled the schools to
adapt in their curricula new features considered desirable in keeping
pace with the rapid increases in medical knowledge and the rising
standards of medical practice. Specially chosen students are given

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- 15 -
special research training to develop their abilities and to stimulate
their interest in research and teaching careers.

This year more than 1,200 well qualified and highly selected
medical students have been attracted into research programs early in
their careers. Some 600 of these students have chosen to study and
work under the direction of pre-clinical science departments. The re-
search fields of anatomy, biochemistry, pathology and physiology are
particularly well represented.

As an example of the stimulation to private funding given by
Federal awards, one school reported that a private foundation has re-
cently provided salaries for four full-time faculty members to expand
its potential for research training.

During the past year a critical evaluation of this program has
been undertaken by an expert committee of non-Federal scientists.
This study will provide the definitive information we shall need when
we discuss with this committee the advisability of expanding or re-
stricting this program. Early progress reports from the study suggest
that the program is extremely valuable and that next year we shall
probably recommend its expansion and establishment on a permanent
basis.

■

The budget proposes $500,000 for the program in 1961, the same
as in 1960.

The program is the subject of a Special Report which is being
provided to the Committee.

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Resear ch Fellowships -- In contrast to the research training
grants, which are made to institutions, the research fellowship
awards are made to individuals in order to maintain a measure of
flexibility in national programming for the support of research
training. The fellowships therefore are considered complementary to
the training awards to institutions. Through five major categories
of awards it is possible to provide spot support for newly developing
areas and to provide special emphasis at a number of education levels
and situations.

The fellowships serve to give students in schools of medicine,
dentistry, nursing, and public health, an orientation to, and an
appreciation of, basic research; to allow foreign scientists to par-
ticipate in the research opportunities in this country, and to
provide firm, long range support for young academic staff members
with a primary interest in research.

For the five fellowship areas the budget provides funds total-
ing $5,310,000 during 1961, the same as in 1960.

I will discuss each of these five areas in more detail:

Regular Research Fellowships -- This program is designed to
help increase the pool of scientists in basic biomedical sciences
and related areas. Research training on a full-time basis in fields
such as experimental pathology, pharmacology, physiology, biochem-
istry and genetics is provided for selected, promising fellows at
predoctoral, postdoctoral and advanced or special levels.

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The predoctoral fellowships emphasize the type of general re-
search training represented by graduate curricula and thesis require-
ments in the basic biological and health-related sciences. The
postdoctoral fellowship makes provision for the increasingly special-
ized research and teaching experience of promising graduates in the
years immediately following the receipt of a doctoral degree.

The development and emergence of new areas in research has kin-
dled interest in many senior, established scientists who may lack
certain basic information or techniques needed to switch attention to
new research fields. Special fellowships are designed to help these
scientists obtain training and experience in these new areas „

It is expected that approximately 216 new regular fellowships
will be awarded during 1960, aside from continuations. The same
level of activity is planned for 1961, with the budget remaining at
$1,035,000, the same as in 1960.

Postso phomore Research Fellowships — The changing character
of the medical and dental schools is attested to today when the supe-
rior student is encouraged to drop his regular work for as much as
three years to carry out full-time research studies in a basic or

pre-clinical science department before continuing his regular medical
studies. The postsophomore fellowship program supports such training
for a limited number of medical or dental students who are selected
by their schools. These fellowships are awarded for a one, two or
three-year period, usually immediately following the candidate's ■

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completion of his pre-clinical studies. They are highly regarded by
the training institution as an effective means for the early identi-
fication of top flight research personnel and their recruitment into
fundamental studies, or for the training of physicians with compe-
tence in medicine and in medical-related investigation.

The increase from $435,000 in 1959 to $575,000 in 1960 permit-
ted 25 additional new postsophomore fellowships to be awarded and
will bring the total for the year to more than 150. A program at
the same level of $575,000 is projected for 1961.

Part-time Student Fellowships — As a companion program to
the postsophomore fellowship, these awards are limited to the sup-
port of students undertaking part-time research training in schools
of medicine, dentistry, nursing, and public health. It is a par-
ticularly effective recruiting device for basic science research,
since many capable students who desire such training may hesitate
or be unable to drop their studies for the full year or more re-
quired by other awards. The program has been well received by
participating schools, since many students thus have been stimulated
into additional research training and study, and have been able to
compete successfully for further fellowship or training awards. A
staff study is underway to identify further the effectiveness of this
program by following the subsequent successes of part-time fellows in
the fellowship and research project competition.

The $300,000 appropriated in 1960 is permitting the support

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and research training of more than 460 new part-time fellows and a
program of the same size is planned in 1961.

Fello wships jfor scientists Jrom other countries -- These
fellowships are awarded to scientists from abroad who desire a year
of advanced study and collaboration with outstanding scientists at
the NIH and at other medical research centers in this country. Since
progress in basic medical research is made on an international basis,
this award promotes a direct and mutual exchange of ideas on technical
accomplishments and scientific outlook. Frequently the international
fellow is well-equipped to make fresh and valuable contributions to
our programs as well as to receive the favorable benefits represented
by experience with the modern technical and scientific activities of
our research scientists.

Candidates for these awards are proposed by a selection com-
mittee within each country, with final selections being made by the
NIH. In 1960 the $400,000 allocated to this program has permitted
the appointment of nearly 60 carefully selected and screened post-
doctoral fellows, and the same size program is planned for
continuation in 1961.

Senior Research Fellowships -- This keenly-competitive and
highly-regarded award program was established to provide support for
academic scientists in the pre-clinical departments of medical and
dental schools and schools of public health. Candidates who show
high promise or exceptional competence are selected on the basis of

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their ability to establish and maintain a strong nucleus of research
activity within these departments while developing themselves as well
rounded academic leaders.

These awards have the additional advantage of helping to re-
lieve the critical shortage of basic investigators in the pre-clinical
departments, as well as providing stability during a critical stage
in the careers of these scientists — that is, the period between the
completion of their postdoctoral training and their eligibility for
permanent senior appointments.

In addition the quality of teaching and investigative work
conducted by personnel located in clinical departments has become an
important feature in modern academic medicine and in the application
of new knowledge gained through fundamental research. In 1961 we
plan to accept applications from clinical departments.

The 1960 appropriation of $3 million is providing support for
95 new senior fellows, bringing the anticipated total to be supported
to 240. The budget proposes continuation of the program at the same
level in 1961.

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CENTER FOR AGING RESEARCH

The Center for Aging Research, which became a component of
the Division of General Medical Sciences a year and a half ago,
has the purpose of stimulating and coordinating research and train-
ing in gerontology both through grants and through direct research
in this field by all the Institutes of NIH.

National and international interest in the field of aging
and in research in aging is, of course, continuing to mount
rapidly.

With regard to research in aging, the growing interest is
reflected in the greater number of scientists who have applied for
NIH grants to carry out work in research in aging in nearly every
medical and biological discipline. Total NIH grant support of
research projects classified as related primarily to gerontology
was $464,000 in 1957; $1,779,000 in 1958; $3,221,546 in 1959 and
a figure of $6,804,000 is estimated for 1960.

If we include, for 1960, those projects classified as
secondarily related to aging, the total will be over $11,000,000.
The intramural work carried out directly by NIH personnel, princi-
pally in the National Heart Institute and the National Institute of
Mental Health, will amount to another $1,000,000 for an over-all
total of approximately $12,000,000.

The Center for Aging Research carries out its work in close
coordination with all the Institutes and with other bureaus and

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divisions of the Department of Health, Education, and Welfare,
including the Special Staff on Aging in the Office of the Secretary;
the Health of the Aged Section in the Chronic Disease Program of
the Bureau of State Services; the Public Health Service Committee
on Aging. The Center is working with the Atomic Energy Commission
in supporting studies of the similarities between radiation effects
and physiologic aging.

Full cooperation is being given to the Federal Council on
Aging and to the White House Conference on Aging. In the latter
instance, the Center for Aging Research staff is providing technical
assistance in planning the agenda of the conference.

Beyond this work with official agencies, we have continued
to cooperate with the great number of private organizations in the
field of aging.

In addition to smaller grants, as you know, NIH has made
grants for two large interdisciplinary research projects in aging,
one to Duke University in 1957, and the other to the Albert Einstein
College of Medicine in 1958. In November 1959 the Duke Center for
the Study of Aging sponsored its First Annual Conference on geron-
tology. Papers were read on subjects ranging from "General Aspects
of Geriatric Surgery" to "Financial Aspects of Aging."

This Conference is the most recent of a number of important
contributions the Duke project already has made to research in
aging. Several research papers on a wide range of aging problems

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have been contributed by the Duke scientists to the professional
literature, and we are looking forward to greater progress in the
forthcoming year. At this point, 20 separate projects have been
initiated under the Duke program. It may be of interest to the
Committee to know that after NIH made its grant to Duke, the Ford
Foundation provided the University with an additional $200, 0C0 for
studies on the socio-economic aspects of aging.

The Albert Einstein project, a year younger than the Duke
program, has completed its work in renovating research laboratory
space for the aging work and has moved from the "tooling-up" phase
into the "tuning-up" phase. Whereas the Duke project is university-
wide in scope, the Albert Einstein program is concentrated in the
Medical School where intense attention can be given to patients in
the Nathan Van Etten Hospital. The City of New York has made a
large ward there available to the program and is providing the basic
medical care needed by the patients. The Albert Einstein project is
seeking a high level of flexibility in its investigations, with
great emphasis on the effort to cut across the dividing lines of
disciplines and departments.

The Duke and Albert Einstein projects have attracted national
attention and we have received applications from a number of other
groups interested in establishing similar multidisciplinary aging
research projects in university settings.

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- 24 -

In addition, of course, the CAR staff is continuing to
encourage more high-caliber individual investigators to work in the
field of aging. I reported before this Committee last year that
we were stimulating additional study into the three broad areas
which are embraced by research in aging: the behavioral and social
sciences , to bring more work to bear in the mental health problems
of older people; the clinical sciences , to help overcome the diseases
which so often characterize old age; and the biological sciences ,
to answer very basic questions related to the exact nature of the
biological process of aging and its relationships with disease.

We have made considerable progress in the past year in
encouraging research along these three lines, but more needs to be
done. Among other plans in the forthcoming year for stimulating
additional research, the Center for Aging Research plans to assist
and cooperate with the Fifth International Congress of Gerontology
to be held in San Francisco in August 1960.

Although aging will be the subject of a Special Report to be
provided the Committee, I should like to cite two or three examples
of the findings that have come out of our research in aging in the
past year.

One investigator has found that a factor closely resembling
the "juvenile" hormone exists in human tissue. This hormone was
discovered in insects, and serves to control the development of the
insects by governing the proper timing of growth from the pupa, or

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- 25 -
cocoon, form, into maturity. It has been found that when this
hormone is injected into certain insects it will allow some growth
to continue, but generally it maintains the insects in a juvenile
state -- having the effect of lengthening the life-span by slowing
down maturity. More research is being carried out to determine
whether, in humans, the hormone is simply a physiological curiosity
of little significance, or whether it has a bearing on the manner
in which man grows old and on the speed with which he ages.

With respect to the common infirmities of older persons,
there has been a clear demonstration in recent years that the
application of intensive rehabilitation techniques will greatly
reduce the disability resulting from these Infirmities. We do not
have any good quantitative measures, however, of the percentage of
older people who can be benefited by rehabilitation techniques, of
the kind and amount of rehabilitation service that is needed, of
the degree of improvement that can be achieved, or of the cost.

In a New York project, investigators are carrying out
intensive studies to answer these questions. Working with groups
of patients in nursing homes, they are developing measures of
disability which are particularly applicable to this group. They
are using rehabilitation teams to treat some of the patients within
the nursing homes, while other groups of patients are transferred
to rehabilitation hospitals for more intensive therapy to see if
the results of such therapy are significantly better. They plan

- 26 -
to follov; all of the patients for a reasonable period after
termination of specific therapy to see how long the effects last.
This study gives promise of producing information that will be of
termendous value in guiding those who are charged with the responsi-
bility of taking care of older people.

The third study, of particular importance to the mental
health of older people, has .shown interesting relationships between
blood pressure and the electroencephalogram patterns. Among older
persons generally the electroencephalogram pattern is more irregular
than among younger people. This study has shown, however, that
older persons with high blood pressure have a more regular pattern
than people of the same age with normal blood pressure. This study
is being continued and if the electroencephalogram patterns are
found to be correlated with actual brain functioning, the investi-
gators may come to the conclusion that a degree of high blood
pressure is sometimes a protective mechanism, rather than being
wholly bad.

These three studies illustrate the scope of research activity
in the field of aging: a study of the biochemistry of aging, a
study of the medical- social treatment of older persons, and a study
of clinical findings.

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- 27 -

CONCLUSION
In conclusion, Mr, Chairman, the appropriation request for
the Division of General Medical Sciences for 1961 is a total of
$44,638,000 as compared with the appropriation of $43,189,000 for
1960. This allowance for 1961 will provide for the continuation of
1960 program levels in all activities and will permit some increase
in grants for research projects. This request for 1961 is distri-
buted among program activities as follows:

Research Projects $26,446,000

Research Fellowships - 5,310,000

Research Training Grants 11,040,000

Experimental Training Grants 500,000

Review and approval 1,342,000

Total $44,638,000

SUMMARY OF OPENING STATEMENT

Director, National Cancer Institute,
Public Health Service

COMMITTEE ON APPROPRIATIONS
196l ESTIMATE
for
"National Cancer Institute"

Mr. Chairman and Members of the Committee:

The research and related programs of the National Cancer
Institute achieved their highest level of operation within the
past year. The budget request for 1961 of $88,869,000 will allow
continuation of these activities at their present level and will
permit some increases in grants for research projects and in dir-
ect research operations.

A brief look at progress in cancer research in the last
decade shows not only a steady advance in fundamental knowledge
of the nature of cancer but also several specific research paths
that make us optimistic about the future. Evidence that cancer
is a manifestation of a basic flaw in the chemistry of the cell
points to the possibility that science will discover new and
vastly effective ways to eliminate cancer by prevention, early
diagnosis, and curative drug treatment. The increased knowledge
of the role of viruses in the production of cancer in animals and
demonstration that some animal tumors can be prevented by vaccina-
tion strongly supnort the hope that at least some forms of human
cancer may also be virus diseases against which vaccination will

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-2-

be effective. Development and application of the cytologic
test for early detection of cancer of the uterine cervix can
lead to the virtual elimination of mortality from this form
of cancer. Cancer chemotherapy has assumed a place of major
importance. Although curative drugs still are lacking , many
cancer patients — especially those with acute leukemia- -have
been afforded longer, more comfortable lives by the use of
drugs .

Numerous laboratory and clinical studies by scientists
and grantees of the National Cancer Institute in the past year
have focused attention on a number of promising anticancer drugs
and on potentially better methods of administering drugs to
patients. The program of the Cancer Chemotherapy National Ser-
vice Center has continued to expand, and 109 drugs are now under
clinical evaluation in studies involving some 7,700 patients.
Approximately 50,000 materials per year are being tested in
animals to identify new active drugs. Serious attention is being
given to attempts to improve the correlation between the res 'Its
of animal studies and clinical experience.

The Institute's diagnostic research program which started
with cervical cytology and which has been shifted to new approaches
is proceeding satisfactorily. Now in its second year is the can-
cer control program of the Bureau of State Services, which is in-
tended to speed the application of proved cancer control measures

-3-

in the general population, and sound initial steps have been

taken to now move ahead with the program.

Interest in the study of viruses as cancer causing agents
continues to be high. Emphasis has been placed on studies of
the relationship of viruses to human cancer. Much additional
information on viruses in animal tumors was accumulated, includ-
ing discovery of a new viral mouse leukemia. The National Cancer
Institute has been instrumental in stimulating research on the
virus-cancer question and is now supporting 110 grants in this
area at a cost of nearly $ h, 000, 000,

The comprehensive program of research and related activities
being conducted and supported by the National Cancer Institute is
steadily increasing knowledge of the nature, cause and prevention,
diagnosis, and treatment of malignant disease. As these endeavors
continue to yield new knowledge, and as this is gradually brought
to practical application, the control of human cancer will become
increasingly complete.

OPENING STATEMENT

Director, National Cancer Institute
Public Health Service

COMMITTEE ON APPROPRIATIONS
1961 ESTIMATE
for
"National Cancer Institute"

Mr. Chairman and Members of the Committee:

It is a distinct pleasure to come again before this Committee
to review the research and related programs of the National Cancer
Institute. I am sure the Committee will share with me the belief
that these activities have brought us substantially closer to the
goal of full and effective control over this awesome threat to the
health and welfare of people everywhere.

Before proceeding with a report to you on the Institute's
diverse activities, I should like to take note of the passing,
within the past year, of three of this Nation's outstanding
contributors to cancer research. Two of these men were struck
down suddenly in the fullness of their careers. Dr. Jesse P.
Greenstein, Chief of the Laboratory of Biochemistry of the
National Cancer Institute, died of a stroke in February 1959*
Dr. Cornelius P. Rhoads, Director of the Sloan-Kettering Institute
for Cancer Research, was the victim of a heart attack in August.
Dr. Dudley Jackson of San Antonio, Texas, who was one of the
earliest and most energetic advocates of a National Cancer
Institute, and long an ardent supporter of cancer research and

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control, died in July. Indeed, it will "be difficult, perhaps
impossible, to replace these leaders. Such men of vision helped
shape the pattern of cancer research as we know it today.

Mr. Chairman, the research programs of the National
Cancer Institute, again this year, reached an unprecedented level
of operation which has been made possible by the steady increase
in Congressional appropriations . We recognize that this growth
carries with it the added responsibility to apply every appropriate
means to finding a solution of the problem of malignant disease,
whether through prevention, arrest, or cure.

DEVELOPMENTS IN THE PAST DECADE
Perhaps an effective way of introducing a discussion of
the Institute's activities would be to look at some of the
accomplishments in cancer research and control over the past decade,
Within the last 10 years, the body of scientific knowledge relative
to cancer has grown, not by dramatic leaps, but in a steady fashion.
Ten years ago, there was relatively little basic knowledge about
the nature of cancer. Seemingly unrelated investigations in
biochemistry, bacteriology, genetics, and virology had not yet
been linked by the realization that these studies pertained to the
nucleic acid of the cell which affects cell characteristics and
reproduction. Now that medical research has yeilded a wealth of
information on the role of nucleic acid in the life and death of

- 3 -

cells , genetics, virology, radiology, environmental cancer research
and numerous other lines of investigation are merging, and the
whole field of cancer research is "becoming more unified.

This synthesis of research has opened up new opportunities
for advances in many fields including chemotherapy and virology,
which I shall discuss elsewhere in this document. Suffice it to
say here that the progress in cancer chemotherapy in the last
decade is marked "by the development of a number of drugs for the
temporary control of human cancer. In 1950, the average acute
leukemia patient survived only a few months after diagnosis.
Today, the average patient may live a year or more. And in
virus-cancer research, new knowledge has led to the development
of vaccines that will prevent certain viral tumors in animals.
There is real hope that research may show that some forms of
human cancer are caused by viruses and that these, too, might
be prevented by vaccination.

The cytologic test for cancer of the uterine cervix has
been proved an effective case -finding technique, and its use can
lead to the virtual elimination of mortality from this form of
cancer.

With the opening of the Clinical Center, the National
Cancer Institute was able to relate closely the study of cancer
in man and the more fundamental, supportive research at the

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laboratory level. This development is representative of a trend
toward greater emphasis on the application of sound scientific
methods in clinical cancer research throughout the Nation.

Another achievement of major importance in the past decade
is the accumulation, for the first time, of a comprehensive body
of knowledge of the epidemiology of cancer. Prior to the
collection of these data, much less was known of the incidence
of cancer by age, sex, race, site, geographic region, etc. Today,
a valuable body of knowledge exists that is being used to explore
the relationship of environmental factors to the causation of
malignant disease.

Because the supply of highly trained scientists in this
country is still far from adequate, the National Cancer Institute
expanded its support of research fellows and, a few years ago,
established a training grants program to assist qualified
institutions in preparing scientists and physicians to enter the
cancer field. Scientists trained in these programs have played
an important part in expanding cancer research during the past
ten years- -this increase in research has been one of the noteworthy
developments of the decade . One measure of this increase in cancer
research activity is the increase in appropriations to the National
Cancer Institute which has risen from $20,000,000 to $91,000,000
between the years 1951 and i960.

- 5 -

The progress made heralds further advances in the years to
come. I should like now, Mr. Chairman, to mention a few examples
of research findings reported "by National Cancer Institute staff
scientists and grantees in the past year and then turn to a dis-
cussion of the special research programs in which the Committee has
expressed particular interest: virus research, diagnostic research,
and cancer chemotherapy.

EXAMPLES OF RECENT RESEARCH FINDINGS

Institute staff scientists have developed a procedure for
testing anticancer drugs in animals in a way that yields precise
quantitatives information about their effectiveness. The agents
are administered to mice that have far advanced leukemia and are
only a few days from death. Drug effect is measured in terms of
lengthened survival of treated animals over untreated controls.
Using this technique, the investigators evaluated a series of
derivatives of methotrexate, the widely used antileukemia drug.
Two of the derivatives, 3'-bromo-5 ' chloroamethopterin and,
3' ,5 '-dichloroamethopterin, produced survivals of 90 days, three
to four times greater than those achieved with methotrexate. Some
animals were still alive 6 months after treatment and were believed
cured. Reinoculation of leukemic cells in these animals failed
to produce the disease, suggesting that they may have "become immune.
One of the two compounds, 3 ' ?5 '-dichloroamethopterin, has been

- 6 -

placed in preliminary clinical trial in the National Cancer
Institute intramural research program and under the program of
the Cancer Chemotherapy National Service Center.

One of the continuing goals of clinical chemotherapy research
is to find ways of enhancing the therapeutic effect of existing
drugs. A group of Institute grantees has reported on studies of
the isolation-perfusion technique for administering anticancer
agents. Essentially the technique involves isolating the tumor-
hearing area (arm, leg, pelvis, etc.) from the normal circulation
stream and introducing into the area relatively high concentrations
of anticancer drugs. Although there is great variation in response
to isolation-perfusion chemotherapy, it appears that this technique
may prove highly valuable in the treatment of certain forms of
cancer.

For the past several years, I have reported to the Committee
on the chemotherapy of a rare form of uterine cancer Known as
choriocarcinoma. As you know, this is one of the few instances
in which treatment with a drug, in this case methotrexate, has
produced complete remission in patients with far advanced,
metastatic cancer. Our experience now indicates that approxi-
mately one-third of choriocarcinoma patients who receive massive
doses of methotrexate experience disappearance of all signs and
symptoms of cancer. One such patient treated at the Clinical Center

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has remained apparently free of disease for more than ^3 months.
The scientists involved in this investigation now "believe that
methotrexate should be considered the treatment of choice for
patients with choriocarcinoma.

Further studies with combination therapy of x-ray and the
antibiotic , Actinomycin D, have demonstrated favorable responses
in patients with certain cancers such as Wilms' tumor and Ewing's
tumor. Simultaneous radiotherapy and chemotherapy in low dosage
appeared to be as effective as higher doses of either component
alone, and somewhat longer therapeutic effects were obtained with
the combination therapy.

A new alkylating agent, cyclophosphamide, is highly
effective in prolonging the survival of mice with advanced
leukemia. The new drug, developed and first tested in West Germany
and marketed in the United States as Cytoxan, has been placed
in preliminary clinical trial against leukemia and various solid
tumors under the program of the Cancer Chemotherapy National
Service Center and the intramural research program of the Institute.

For the past several years, the incidence of stomach cancer
in the United States has been downward. In contrast, cancer of
the lung has been increasing. It is interesting to note that
cancer of the female breast, the leading cause of death from
cancer among women, remains relatively unchanged. Institute

- 3 -

scientists, in collaboration with investigators of the
Connecticut State Department of Health, reported within the
year that survival among breast cancer patients has remained
stable for about a quarter of a century. This finding leads the
scientists to the conclusion that any substantial improvement
in this form of cancer is more likely to result from the develop-
ment of new forms of treatment rather than from further modi-
fications and refinements of existing methods.

VIRUS RESEARCH
Research on the possible relationship of viruses to human
cancer has rapidly become one of the most active and provocative
areas of the National Cancer Institute's program. Several months
ago, a scientist in the Institute's Laboratory of Biology reported
the discovery of a new virus-induced tumor that we believe is of
particular importance. This fascinating study began with an
investigation of some of the properties of Sarcoma 37 ;> an experi-
mental mouse tumor. In the course of this work, the investigator
prepared a cell-free extract of the tumor and injected it into
healthy mice. The result was entirely unexpected. Within eight
months, the injected mice developed leukemia of a type virtually
indistinguishable from the spontaneous form of the disease in mice.
Following this new lead, the scientist prepared fresh extracts
from leukemic tissue of the animals that first developed the

- 9 •

disease and injected these into mice. After several of these
so-called selective passages/ an extract was obtained that
causes leukemia within 10 weeks in 100 percent of the mice
injected on the first day of life. The leukemia-producing
agent in the extract is a virus, which has been seen under the
electron microscope. In contrast to other leukemic viruses
affecting mice, this new agent elicits the disease in several
different strains and is active in adult as well as newborn
animals. None of the injected mice has developed any form of
cancer other than leukemia.

Discovery of this new virus leukemia is particularly
important at first, because it provides additional information
about the role of viruses in animal cancer, and second, and perhaps
more important , because it may become an extremely valuable model
test system for use in further research on the human virus-cancer
question.

I am glad to report that our grant -supported virus research
is going very well. There are now in effect 110 grants for
studies in this area, and their total value is nearly $4,000,000,
which is about a twofold increase in the past year alone. Among
the investigators who are participating in this expanded program
are many virus experts who are entering the cancer field for the
first time .

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The phase of virus-cancer research into which we are now
entering presents a number of problems and obstacles which
necessitate some modifications in our attitude toward grants
for virus research. For example, greater consideration is being
given to long-term support of the scientist himself rather than
to the specific virus research project he proposes to undertake,
because of the complexity and difficulty of virus research,
particularly in man. Support for some of these virus studies has
been recommended for periods up to 10 years . We agree with our
advisors that these attitudes and practices are decidedly
important if virus-cancer research is to be pursued in the most
wise and productive manner.

The many and varied problems confronting scientists in
the conduct and future course of research on the relationship of
viruses to human cancer were discussed at a recent meeting in
Rye, New York, held under the auspices of the American Cancer
Society. It was attended by many of the Nation's leading in-
vestigators in the virus-cancer field, most of whom are grantees
of the National Cancer Institute.

At first glance, it would appear relatively simple to
establish the role of viruses in the production of human cancer.
One would have only to find viruses in malignant tissue and then
demonstrate that they had caused the disease . This is an extremely

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complicated task. Even though virus-like particles have been seen
in electron microscope pictures of human leukemic tissue., scientists
are still confronted with the extremely difficlt task of demonstra-
ting whether a virus that may be isolated from human tumor tissue
is indeed the causative agent. The fundamental problem lies in a
lack of an established means of testing the carcinogenic effect of
viruses on humans. Therefore, an important goal is the development
of laboratory techniques that will attack the problem indirectly.
We believe that significant progress has been made in the
fundamental studies that are needed to equip us with knowledge to
investigate the virus-cancer problem. For example, the number of
laboratories where human cells are being grown in tissue culture
has greatly increased in recent years, and this has facilitated the
search for and study of carcinogenic viruses in human tissue. Other
work is steadily expanding knowledge of the chemical and biological
nature of viruses and their behavior within cells. The discussions
at Rye indicated that some progress is being made in clarifying the
biochemical association of viruses to the innermost constituents of
the cell. This work is aimed at finding out how viruses might enter
a cell and make it cancerous. Just how this might happen remains to be
explained, but there is evidence, based on studies in bacteria, that
a virus may entwine itself in the cell's genetic mechanism and so
modify it that the cell begins to reproduce abnormally. Or, a virus
may enter a cell, attach to itself some of the cell's genes, and transport

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12 -

them to a second cell, again causing an abnormal , malignant
change. There is support for the suggestion that a dormant
virus hidden within a cell may be activated by some external
agent, such as x-rays, and thus start the process of malignant
growth.

Each of these possibilities and many others need to be
thoroughly investigated in order to gain precise knowledge of
the virus-cancer relationship. Scientists must learn much more
than is now known about the so-called "model virus tumors," the
role of immunity, the significance of other non- cancer producing
viruses present, the effect of antibody formation, the influence
of one virus upon another, and a host of other facts.

Furthermore, adequate supplies of laboratory materials
essential to research on the role of viruses in human cancer must
be made available. Among these are "banks" of normal and malignant
human tissue, several of which are now in operation, and uniform
preparations of virus materials. The Institute, under guidance
of the recently formed Viruses and Cancer Panel, has taken steps to
establish two tissue-culture cell banks, which now make available
to investigators cells of known properties. Selected cell strains
will be kept for long periods in a frozen state to serve as
reference materials. Tumor viruses and antisera against them will
also be preserved in the same way.

- 13 -

What could medical science do if cancer were proved
to be a virus disease? You will remember, I touched briefly
on this question last year. At that time I suggested that it
might be possible to develop a vaccine that would prevent man
from developing cancer. We should consider, though, that it
might take many years to determine the effectiveness of a human
anticancer vaccine, were one developed. On the other hand,
if acute leukemia, for example, were found to be a virus disease,.
we would probably know within a few years whether a vaccine
administered to babies was effective, because this form of
cancer most often strikes young children. It should be pointed
out that the isolation and identification of a cancer-producing
virus may not lead to the quick development of a vaccine.
Viruses differ in the properties that determine the ease
with which they can be used in the preparation of vaccines.
I reported last year that some success had been achieved in
detecting antibodies against the polyoma virus and preventing
tumors in hamsters following injection of the virus. On the
other hand, attempts to detect antibodies against the mouse
leukemia virus mentioned earlier have so far been unsuccessful.

Moreover, the steadily growing body of knowledge of the
oiochemistry of viruses and their effects upon cells may
eventually permit the development of antiviral drugs. Laboratory
studies have shown, for example, that a virus that infects

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bacteria can induce the formation of an enzyme necessary for
reproduction of the virus within the cell. A potent anti-
tumor agent, 5-fluorouracil deoxyriboside, blocks this newly
formed metabolic pathway by combining with the enzyme. Thus,
the drug selectively attacks only the bacteria infected by
virus.

Additional virus research accomplishments within the
year include : National Cancer Institute - Division of Biologies
Standards studies showing that the polyoma virus is a single
organism rather than' a group of viruses each of which induces
malignancy at a specific site; immunization of female hamsters
during pregnancy substantially reduces the incidence of tumors
in offspring challenged at birth with polyoma virus; human cancer
cells can be grown in a tissue culture medium free of blood serum
and, therefore, also presumably free of certain virus inhibitors
that may be present. An Institute grantee succeeded in growing
human cancer in previously untreated laboratory animals by
injecting the malignant cells into fetal rats a few days prior
to birth. Because the fetal animals apparently lack natural
resistance to foreign transplants, the cells were able to multiply
and continued to grow after birth. If perfected, such a technique
may be of value not only in human virus-cancer research, but in
chemotherapy, and other areas of investigation. ■

- 15 -

The implications of this work in viruses and cancer
are literally "beyond imagination. Yet, it does not appear
unreasonable to anticipate that research on the relationship
of viruses to cancer may ultimately lead to a completely new
and highly effective means of preventing or arresting the
development of human malignant disease . I am glad to say that
the National Cancer Institute is making an important contribution
toward the accomplishment of this goal.

DIAGNOSTIC RESEARCH
At the appropriation hearings a year ago, I reported to
the Committee that steps had been taken to initiate a program
of intensive research to develop improved tests or other procedures
for the detection of early cancer. As of December 1, 1959 > "ten
contracts and several other direct cooperative projects were in
effect. One aspect of the work in progress is biochemical studies
to determine differences in the distribution of enzymes and other
elements in the blood of cancer patients and other persons, in an
attempt to identify some consistent characteristic of the blood
of cancer patients that can be detected before overt symptoms
appear. With essentially the same objective in view, other
studies are attempting to develop the technique of fluorescent
microscopy so that it can be used to detect early cancer. Research
is continuing in an effort to assess the significance of malignant

- 16 -

cells in the peripheral blood of cancer patients. As yet, it
is not clear what interpretation can be placed on the findings
of malignant cells in the blood stream.

We will continue to make use of the grants mechanism to
provide support for fundamental studies in the area of cancer
diagnosis, and we will utilize our contract authority for other
studies that are best suited to this form of support.

In addition to the diagnostic research program per se ,
a number of other developments in the area of cancer detection
deserve special mention.

Thanks largely to the work of the Field Investigations
and Demonstrations Branch over the past several years, the
cytologic test for detection of early cancer of the uterus has
been established as a reliable procedure for detecting this
form of cancer at a stage when it is virtually 100 percent
curable. Further research in this area has been designed to
obtain more complete cytological, epidemiological, clinical,
and pathological information on uterine cancer. Significant
information gained from these studies is being made available
to operating programs for general application as new techniques
are developed and proved effective. As reported previously,
efforts are under way to devise methods of applying cytology
to the detection of early, symptom-free cancer of other sites ,

- 17 -

such as the colon, lung, stomach, urinary system, and prostate.
Three such projects are in progress at this time: colon and
large bowel cytology at Ohio State Medical School, Columbus,
Ohio; lung cytology at the University of Texas, M. D. Anderson
Tumor Clinic and Hospital, Houston, Texas; and gastric cytology
at the Bowman-Gray School of Medicine, Winston-Salem, Worth
Carolina.

Another important aspect of our continuing cytologic
research activity involves development of the cytoanalyzer .
A large-scale, clinical trial of this instrument involving
approximately 10,000 vaginal specimens is now in progress and
is expected to complete the developmental work with the
cytoanalyzer, so far as uterine cytology is concerned. It is
anticipated that this field trial will he completed late in
I960.

CANCER CONTROL PROGRAM
In fiscal year i960, the Cancer Control Branch of the
Bureau of State Services, U. S. Public Health Service, will
comp3.ete its first year of operation. This program is conducted
under the technical guidance of the Director of the National
Cancer Institute. The program is devoted to strengthening the
Nation's cancer prevention and control efforts, with the State
health departments as a pivot around which these activities will
be developed.

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- 18 -

A series of regional meetings is being held with represent-
atives of medical groups from "both private practice and public
health. These discussions have helped identify opportunities and
obstacles in extending community cancer control work and have
contributed to the creation of a national effort among the various
professional groups with interests in this program.

One of the first goals of a program of this kind is to
assess the present state of cancer control activities at the
local level. Reports on the current conduct of State health
department plans and projects, the nature and extent of
facilities, and the availability of nursing education courses
in cancer control are being prepared for publication.

Naturally, the success of a cancer control program depends
largely on the communication of useful information about the
disease to the general public . To explore and evaluate ways of
reaching different population groups and to enlist their cooper-
ation in uterine cytology screening programs, pilot projects
are being carried out in a number of cities throughout the
country. In this way, information is being gathered on
successful and unsuccessful methods of encouraging women of
differing backgrounds to avail themselves of the cytologic test
for uterine cancer. These projects also provide training for
medical, nursing, and related personnel in current cancer
detection techniques.

:;>_

- 19 -

An important component of the Cancer Control Program is
the Cancer Community Demonstration Project Grant Program, which
is intended to help local communities to apply proven control
measures. Emphasis is being concentrated on developing projects
in prevention, public and professional education, early diagnosis,
case reporting, and rehabilitation. Professional and voluntary
agencies, as well as State and local health departments and
community hospitals, are "being encouraged to participate in
this work. Applications for project grants are reviewed "by the
appropriate State Health officer, by the Advisory Committee to
the Control Program, which includes nonfederal consultants in
the medical sciences, public health administration and related
fields; and by the National Advisory Cancer Council. It is
anticipated that 30 to kO such projects will be supported
during the 1961 fiscal year in communities throughout the
country.

CANCER CHEMDTHERAPY PROGRAM
The program of the Cancer Chemotherapy National Service
Center is now in its fifth year of operation and a considerable
body of information has accumulated which is now permitting
comprehensive reviews and analyses not previously possible.
They are being undertaken to insure that the chemotherapy activity
maintains its present well-rounded mode of operation and that no
major areas are being inappropriately neglected or overemphasized.

- 20 -

Synthetic chemicals and antibiotic materials are "being
screened at the rate of about 40,000 a year. These are
supplied by contractors engaged in synthesis work, by ''prep lab"
contractors who furnish commercially unobtainable compounds, and
by universities, research institutions, and industrial firms.
During the present calendar year (i960), an additional 500
synthetic compounds per month will be screened in tissue culture
rather than in the conventional mouse tumor system since
insufficient quantities are available for the primary animal
screen system. In addition, the screening of plant materials will
receive increased attention in the coming year. This is a new
source of materials and is of interest because of activity
already found in several plant products.

Handling of the large, and constantly growing, volume of
information created by the primary screening operation was made
largely automatic within the year by the activation of a new
electronic data processing machine. This will make possible the
rapid return of information on screening results to the suppliers
of test materials.

In order to achieve the high level of screening activity
commensurate with the supply of new materials, it has been
necessary to increase production of inbred animals. Since the
inception of the chemotherapy program x the supply of animals has

- 21 -
risen frcm a level of 100,000 per year to more than 1,500,000
per year. Standards to protect the quality of laboratory
animal production and effective methods to control disease
among such animals have been established.

The clinical trials portion of the Service Center's program
has attained an unprecedented level of operation in terms of the
numbers of studies, investigators, new agents, and patients in-
volved. At present there are 17 clinical groups participating
in the program in ikj hospitals, including public and private
institutions, Veterans Administration hospitals, and the Clinical
Center of the National Institutes of Health.

There are now 109 drugs in various stages of clinical
evaluation in studies involving some 7>700 patients. These include
53 steroids and hormones, 22 alkylating agents, 8 antibiotics,

16 antimetabolites, and 10 miscellaneous agents. Plans are now
being made to accelerate the clinical evaluation of drugs. During
the 1959 calendar year, preclinical evaluation was completed on 10
new agents that appear to warrant testing in man. At present,

17 other new compounds are in various stages of preclinical pharma-
cology and should be available for clinical trial within the next
six to twelve months . :

Perhaps the chief problem in the chemotherapy area that
awaits solution is the lack of satisfactory correlation between

the results of drug testing .in animals and clinical trials.
This point was strongly emphasized at the first Conference
on Experimental Clinical Cancer Chemotherapy, which was held
recently in Washington under the sponsorship of the Service
Center. Some 63O clinicians and other scientists participating
in the national chemotherapy program attended the two -day
conference and heard reports on the status of the cooperative
clinical trials and other aspects of the program. The view
was expressed by many speakers that better statistical
correlation between animal and clinical studies will be
possible as more clinical experience is gained with the drugs
now available, and as this experience is analyzed by precise
statistical methods. Another approach to this problem which
is under careful consideration is the addition of more animal
tumors to the primary screening process. The objective here
would be to attempt to relate to human tumors the response 00
chemotherapy of particular animal tumors. Some initial work
along thj.s line has been encouraging/, and we may hope that
further efforts will produce a screening system that enables
excellent prediction of drug action in man.

The bulk of the program administered by the Service
Center, apart from clinical trials, is being carried out under
contracts with industry, non-manufacturing research insti-

- 23 -

tutionsj, colleges, and universities. There are 108 chemotherapy
contracts in effect and many of the Nation' s leading
pharmaceutical firms are actively engaged in contractual
chemotherapy research.

The chemotherapy program has encouraged more scientists
to undertake the study of cancer than might have done so other-
wise, and has achieved a more universal definition of the cancer
problem and approaches toward its solution. The program has
provided training for hundreds of scientists and physicians
not only in cancer research hut in the basic sciences generally.
It has contributed to fundamental chemistry through the develop-
ment of new and unusual methods of chemical synthesis and the
production of large quantities of unique compounds. It has led
to the organization of a national, standardized system for
reporting end results in cancer, thus providing a base line
of the effect of treatment in more than 50,000 patients a year.
The clinical trials are introducing sound research methodology
in the clinic to many young physicians who otherwise would
not have received such research training. These are only a
few of the byproducts of the national cancer chemotherapy
research program.

The Cancer Chemotherapy Program has and is being studied
to determine whether steps can be taken to improve it and the

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chances for finding fully effective anti-cancer agents. We
know that our screening techniques fall far short of the ideal.
Yet most of those who know this field and program believe that
the substantial investment in this program is warranted even
though no -one can predict that the cure for cancer will come
from the largely empirical approach which characterizes this
program.

TRAINING
Dr. Shannon has discussed the importance of training
programs to medical research progress. Those of us in cancer
research are convinced that training must continue at a high
level in the scientific disciplines concerned with the life
sciences, for the great majority of these are required for
cancer research. In addition, the training programs supported
by the National Cancer Institute concentrates on cancer as a
specialized problem in itself, and encourages competent
scientists to make a career of cancer research.

Dissemination of information continues to be a constant
and burdensome problem affecting virtually every branch of
scientific inquiry. Delay in publishing reports in the scientific
literature is a major problem. Because of such delays, scientists

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- 25 -

may embark on carefully planned research projects only to find
too late that other investigators have already covered the
ground. One step taken to shorten the lag in publication of
papers in the cancer field was the conversion of the Journal
of the National Cancer Institute from a bi-monthly to a monthly
publication. Now the Journal is being expanded further from
2,1+00 to 3,000 pages per year. Even so, it is estimated that
there will still be substantial delays in publishing worthwhile
reports. To minimize these delays, reports of seminars and
review papers of considerable length are to be published
separately as monographs .

We are continuing to utilize every available opportunity
to improve and increase cancer research internationally. Many
of our staff scientists have traveled to foreign nations to
attend scientific meetings and exchange information with cancer
investigators in other lands. Numerous visiting scientists
have come to Bethesda to work in our laboratory and clinical
facilities, to learn from us, and to give us the benefit of
their experience.

Of particular interest and importance this year were
two international conferences on the evaluation of end results
in the treatment of cancer. Scientists from England, Denmark,
Finland, France, Norway, Russia, and the United States met with

- 26 -

members of the National Cancer Institute staff tc discuss
plans for cooperative studies on end results, epidemiology,
and incidence of cancer in various population groups through-
out the world. A program of comparisons of end results in
cancer is being planned fo? the Eighth International Cancer
Congress, to be held in Moscow in 1962. Such comparisons
should facilitate the application throughout the world of
techniques found superior by workers in one country. Plans
are being completed for the Fourth National Cancer Conference,
which is held every four years under the auspices of the
National Cancer Institute and the American Cancer Society.
The meeting will be held in September I960 in Minneapolis
and will be oriented primarily to the interests of clinicians.
Outstanding authorities will discuss such topics as causation,
control, and treatment of cancer under the general theme,
"Changing Concepts Concerning Cancer. "

CONCLUSION
In conclusion, Mr. Chairman, the appropriation request
for 1961 is a total of £88,869,000 as compared with the
anticipated obligations in I960 of $87,757,000. This
allowance for 1961 will provide for the continuation of I960
program levels in all activities and will permit some increase
in grants for research projects and minor increases in the

- 27 -

direct research activities of this Institute. This request

for 1961 is distributed among program activities as follows:

Grants :

Research projects #35,941,000

Research fellowships 1,912,000

Training 7,055,000

State control programs 2,250,000

Community demonstration projects 1.500,000

Total grants 48,653,000

Direct Operation s;

Research 12,395,000

Review and approval 1,032,000

Professional and technical assistance - 5,217,000

Chemotherapy contracts 21,145,000

Administration 422,000

Total direct operations 40,211,000

Total appropriation 88,869,000

Under the budget we can increase our investment in
research projects by f. 578, 000. An additional $45,000 will
permit payment of full indirect costs on research projects awarded
on and after January 1, 1961. It also provides for an increase

of $300,000 in direct research activities. These additional

- 28 -

funds would be used for relocating our tissue preparation
laboratory now housed in a temporary building which is to
be torn down upon the completion of the Office Building; for
expanding radiation studies, and for publication of the
increased volume of scientific information.. Other changes
in the budget relate to mandatory items and increases in
reimbursement to the management fund and to decreases for
non-recurring items. The net result ia an increase of
$1,112,000 in obligations over i960 and a decrease in the
total appropriation of $2,388,000.

Now, Mr. Chairman, I shall be happy to answer any
questions or aid in further discussion.

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SUMMARY OF OPENING STATEMENT

Director, National Institute of Mental Health
Public Health Service

COMMITTEE ON APPROPRIATIONS
1961 ESTIMATE
for
"Mental Health Activities"

Mr. Chairman and Members of the Committee:

During the past four years there has been marked expansion
in all of the Institute's programs and many important new ways
have been developed to help meet the challenge of mental health
problems. During these years, the resident populations in the
public mental hospitals have steadily declined. However, the
number of admissions to these hospitals is still rising and,
despite many favorable developments, the public health problems
posed by mental and emotional disorders are still large and
pressing. To help cope with these problems, the Institute has
employed a dual approach in each of its major programs — attempting
to find better ways of treating mental and emotional disorders
which have already developed, and also attempting to develop
effective preventive measures.

Mental health project grants, grants in psychopharmacology,
program grants, and career investigator grants have significantly
enlarged the scope of research supported by the Institute. More
emphasis has been placed on developmental grants in such important
areas as juvenile delinquency, alcoholism, school mental health,

- 2 -

and mental retardation. Biological and social scientists have
become increasingly interested in doing mental health research
and many other new types of investigators are being drawn into
work in this field.

The Institute's intramural research work has likewise been
broadened during the past few years. The Clinical Neuropharmacology
Research Center located at Saint Elizabeths Hospital permits the
Institute to study large populations of patients and to test
therapeutic measures in a public mental hospital setting. The
Institute is doing work on normal child development, patterns of
family living, psychosomatic mechanisms, and biological aspects of
schizophrenia. Other important areas of investigation include
basic metabolic studies, intensive investigation of areas of the
brain which control important aspects of human behavior, and
fundamental studies of the chemistry of the body utilizing psycho-
pharmacological substances as research tools.

During the past year, important progress was made in research
which attempts to establish causal relationships between biochemical
processes and mental disorders. Research done under the auspices
of the National Institute of Mental Health has pioneered in the
establishment of better criteria on which to base such studies.
The functions of various parts of the brain are being mapped by
Institute grantees and for the first time during the past year
support has been provided for a long-term program of combined

- 3 -

behavioral, anatomical, and neurophysiological studies in "split-
brain animals." New biochemical methods are being used to measure
emotional aspects of behavior and the Institute is supporting
several studies on hereditary aspects of mental illness.

The scope of the training grants program has also widened
considerably during the last several years, and support for
training has been extended to the 1 asic biological, behavioral,
and social sciences, as well as to more varied areas of psychology,
psychiatry, nursing, and social work. There has been an increase
in support of training for research as well as for clinical work.

During the past year support of research training was
broadened to include all four mental health disciplines. Also
a large proportion of awards for research training in the
biological sciences placed considerable emphasis on psychopharma-
cology. The Institute's psychiatric training program for general
practitioners was received enthusiastically by the medical pro-
fession. This training activity is especially important since
it is estimated that 90 percent of all psychiatric problems
receiving medical attention are handled by the family physician.
During the past year increased support was also given for
psychiatric training in medical schools, nurse training centers,
and graduate schools of social work.

The technical and professional assistance provided by
Institute staff and the financial help of Federal grants-in-aid
have stimulated the development of more adequate State mental health

- k -

programs. Technical assistance projects have been utilized by
the Institute to help States strengthen their community mental
health programs. Broad community-based programs are beginning
to develop and there is greater recognition, on the part of
leaders in education, industry, and other important segments of
the community, of their responsibility for mental health work.

The Institute's activities in the field of alcoholism
were markedly expanded during the past year. The five-year grant
to the North American Association on Alcoholism Programs will open
the way for a reexamination of the entire problem of alcoholism
and permit a unified and impartial approach to this urgent and
costly problem.

At the request of Congress, the Institute, in collaboration
with the Children's Bureau, has conducted a study of the problem of
juvenile delinquency and is preparing a report which attempts to
answer the question: What can and should be done in the field of
juvenile delinquency?

The report includes both substantive and fiscal proposals
for action. In the mental health project grants program, which
supports studies aimed at developing new and improved methods
for the care, treatment, and rehabilitation of the mentally ill,
special consideration has been given to projects which impinge
on critical problem areas such as schizophrenia, alcoholism,
juvenile delinquency, mental retardation, and aging.

- 5 -
The Institute's Psychopharmacology Service Center has helped
to stimulate research by working with and providing technical and
professional assistance to individual investigators and small
groups of researchers focusing on specialized problems. The
effectiveness of these efforts is evidenced by the increased amount
of psychopharmacological research. During the past year, a con-
tract was awarded to support work on the synthesis of certain indole
derivatives to be used in basic research. Work is proceeding in
three major areas: (1) evaluation of the clinical efficacy of
drugs in treating psychiatric conditions; (2) development of better
methods for testing drugs at the preclinical level; and (3) inten-
sive study of the biological mechanisms through which known psycho-
active drugs produce their effects.

Conclusion
To continue the vital work of the Institute and consolidate
the gains made during the past year, the appropriation request for
1961 is a total of $67,563*000. This compares with the appropria-
tion of $68,090,000 for i960. This allowance for I96I will provide
for the continuation of i960 program levels in all activities. An
adjustment downward of $3,850,000 reflects the nonrecurring adjust-
ment of project period starting dates of training grants. An
increase of $3,208,000 will be available for additional support of
research grants.

- 6 -
The request for 1961 is distributed among program
activities as follows^

Research projects $26,690,000

Research fellowships 1,996,000

Training grants 22,356,000

State control programs 5*000,000

Research 7,697,000

Review and approval of grants 1,293,000

Training activities 100,000

Professional and technical assistance .. 1,926,000

Administration 505,000

Total $67,563,000

OPENING STATEMENT

by
Director, National Institute of Mental Health
Public Health Service

COMMITTEE ON APPROPRIATIONS
1961 ESTIMATE
for

"Mental Health Activities , Pablic Health Service"

Progress in the field of mental health has proceeded at an
accelerated pace during the past 3 or k years. Since fiscal year
1957 j there has been a markedly expanded program of research,
training, consultation, and other developmental activities in
mental health. These years have also seen important new trends
in the ways in which the National Institute of Mental Health has
organized its programs to help meet the challenges and the many
unsolved problems of mental health and mental illness. I should
first like to address myself to the developments during these years.

New Trends and Program Developments
Research Grants

New type s of progrs-ms have been made possibl e. The kinds
of programs and activities supported by research grant funds have
increased significantly beyond individual basic and clinical research
projects. The Mental Health Project Grants and grants in psycho-
pharmacology make possible a broad attack on problems of care,
treatment, and rehabilitation of the mentally ill, and have stimu-
lated evaluative studies of drug effectiveness. Program grants

- 2 -
permit teams of highly competent investigators a greater degree
of freedom in;. -pur suing a variety of important". 'broad studies.
Career investigator grants have helped fill the need for
sophisticated psychiatric research personnel. These developments
have done much to enlist the collaboration of research centers in
new areas of particular concern to the mental health field. The
support of individual projects has not suffered as a result of
these developments. The increased appropriations during the past
5 years have made the new developments possible concurrently with
the normal growth in research organized by specific projects.

More em phasis has been possible on developmental grants in
areas of special public concern . The Institute has been enabled to
work in close collaboration with several universities, mental
hospitals, and other groups on large-scale studies to explore such
areas as psychiatric rehabilitation, mental deficiency, juvenile
delinquency, aging, alcoholism, and mental health in schools and
in industry. These activities define new problems for research as
well as new emphases in mental health programs, and result in
generally increased mental health activity. The Mental Health
Project Grants have encouraged the improvement of programs for the
mentally ill through a variety of projects, including demonstrations,
research, and evaluation studies. These grants have acted as a
catalyst for such programs, increasing the interest and vigor of
the staffs, enabling them to retain a higher level of personnel,

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and fostering closer relations between mental hospitals and
universities. Grants in peychopharmacology have made possible a
more orderly development in a field of great promise.

The Institute has also been able to provide funds for
supporting activities, such as research conferences, abstracting
services, development of regional cooperation through such agencies
as the Western Interstate Commission on Higher Education and the
Southern Regional Education Board and assistance to organizations
like the American Association for Mental Deficiency and the National
Association for Retarded Children so that they can provide the
necessary leadership to professional workers in key mental health
problem areas .

The horizons of research in mental health have been widene d.
There has been a marked increase in interest in research in mental
health in the biological and social sciences. In addition, leaders
in the fields of education, industry, public health, welfare, and
vocational rehabilitation are beginning to recognize the importance
of mental health considerations in their programs and are welcoming
pilot studies. These developments have occurred concurrently with
the steady pattern of growth of research in psychiatry, psychology,
and the other behavioral sciences, and point toward a further
broadening of research in mental health in the future.

New groups are becoming involved in research . All of these
changes have resulted in drawing new types of workers into mental

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health research. Younger investigators who have done research as
graduate students, or as young faculty members worked on grants under
the direction of a senior investigator, are now applying for and
receiving grants of their own. More social scientists and biologists
are applying for and receiving grants. Social workers, nurses,
vocational rehabilitation personnel, and other service professions are
becoming interested in and are doing more research. Thus there is a
growing manpower pool available for research in areas of increasing
public interest and concern.
Training Grants

The areas of support have been broadened . High priority
initially was given to training in the clinical areas of psychiatry,
psychology, social work, and nursing, because of acute shortages of
these personnel. But a need also was recognized for training in other
areas. Increased appropriations have made it possible to support
training in a broader range within psychology and social work. Basic
biological and social sciences, and undergraduate psychiatry and
nursing have been added to the program of support. A new program
developed for training general practitioners has received a markedly
favorable response from the medical profession. These developments
help to meet the increasingly recognized needs for people with mental
health orientation who have the widely varied skills required for
professional work in such fields as family life, child development,
institutional management, and community interaction. They go beyond

- 5 -
planning to meet the needs for early treatment and aim at the emergence
of a "broad preventive program. Specialists in the biological and
behavioral sciences are becoming a regular part of the faculties of
medical schools , usually working closely with the departments of
psychiatry.

Clinical training in the core mental health professio n? h '3S_
also i nc rea sed. The needs for training clinicians to deal with the
problems of those who become mentally ill or seriously disturbed
emotionally have not lessened. By 1957 "the training center had
reached a point where the potential was available for a marked
expansion in the training program, including significant increases in
traineeships as well as expanded teaching staff. Since that time,
increased appropriations have made it possible to take advantage of
this potential.

There has been an increase in training for research . The
expanded spectrum of research in mental health has required a parallel
increase in training. New programs are being supported in research
training in the four core disciplines and in various biological and
social sciences of relevance to mental health. The number of research
fellowships has markedly increased, both for predoctoral and for
special advanced training.

Increases in staff have enabled more effective collaboration
b etween the Institute and the training centers , Training programs must
be carefully planned on a long-term basis. Primary responsibility for

-!•':

- 6 -
such planning lies, of course, with the training centers themselves,
but they welcome the consultation of training specialists from the
National Institute of Mental Health. These specialists also provide
analyses useful for maintaining balance in meeting needs for training,
research, and service.
Community Services

Broad community -based programs are beginning to develop . Clinics
are becoming part of such programs and are providing consultation
services as well as individual treatment for patients. Mental hospital
personnel are beginning to collaborate with agencies in the community.

Recognition of responsibilities for mental health has broadened .
A recent survey of public health personnel indicated that mental health
was considered to be the most important problem area. Responsibilities
are being decentralized. A greater awareness has developed of the
importance of preventive services and of aftercare for the mentally
ill.

Technical knowledge is growing in relation to special problem
areas . Technical Assistance Projects, in collaboration with the States,
are helping to develop better, mental health programs in such areas as
school and industrial mental health, alcoholism, and aging.

A ll States are benefited . In some States virtually no mental
health services existed until the last decade. Increases in grants-
in-aid have enabled these States to make important beginnings.

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Increase in staff ha s provided more effective demonstrations
and consulta tion. The Institute's Mental Health Study Center in
Prince Georges County, Maryland, has pioneered in the development of
a public health approach to problems of alcoholism. A local hospital
and an outpatient clinic are collaborating with private physicians
in case -findings, services to affected families, and rehabilitation of
alcoholics. Increased staff in the Regional Offices has made consul-
tation possible in relation to new experimental programs. The
central office is able to do a more effective job of program analysis
and of consultation on evaluative studies.
Biometrics

Modest increases in the Institute's biometrics staff have
permitted expansions and improvements in the important field of
reporting basic data concerning the incidence, prevalence, and
treatment of mental and emotional disorders. Consultation service
has been given to l6 States to improve their reporting systems. The
Model Reporting Area for mental hospitals has increased from 18 to
22 States since 1957. The hospitals in these States provide care
for 75 percent of the patients in State and County mental hospitals
in the United States on any one day. These 22 States spend approxi-
mately $650 million annually for the care and treatment of patients
in their State and County mental hospitals; this represents "J6 per-
cent of the total spent for all State and County mental hospitals in
the United States. The number of clinics reporting data relating to

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patients has increased from U00 to approximately 1,000. The
biometrics staff has initiated a program in one State, on a pilot
basis, of reporting data concerning patients from all facilities
providing psychiatric care in the community. The staff has
collaborated with staffs of the American Psychiatric Association
and the World Health Organization in revisions and development of
systems of statistical classification of mental disorders.
^■^d^rjr-" 1 - Clin leal Investi gation s

The establishment of the Institute's Clinical Neuropharma-
cology Research Center, located at Saint Elizabeths Hospital, has
been a ma,}or development. The Center provides the opportunity to
study large patient populations and to test new and old methods of
therapy in a public mental hospital setting. A group of laboratory
scientists has been brought into direct contact with problems of
mental disorders, and this has influenced the formulation of some
of their research problems. The program of Clinical Investigations
generally has expanded to include studies of normal child development,
of successful coping behavior in adolescents, and of patterns of
family living, thus providing control populations in which those
factors responsible for adaptive and maladaptive behavior may be
identified. In keeping with the interdisciplinary character of the
Institute's research program, considerable emphasis is also being
placed on the biological aspects of behavior, and of schizophrenia
in particular. The mechanisms by which emotions influence somatic

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responses are being studied, and knowledge is being acquired
about tbe way in which amino acids and certain amines of relevance
to the brain, such as adrenaline, are handled in normal and
schizophrenic individuals.
Intramural Basic Resear ch

A new resource, a small research greenhouse, has made
possible the initiation of research, using plants, on a number of
important problems, particularly the biosynthesis of alkaloids. An
important discovery already has been made that methylation processes
important to activation and inactivation of many pharmacological
agents take place by way of the same biochemical steps in plants
and single -celled organisms as in higher mammals, including man.
This opens the way to studies of certain key metabolic processes
starting with plants, where control of growth, harvesting, and bio-
chemical separation of products is simpler than with animals. Easic
studies are continuing on protein synthesis, on the biochemical
mechanisms underlying the catalytic action of certain large mole-
cules, and on the way in which nucleic acids may order the sequence
of amino acids in proteins and hence transmit genetic information.

Analyses of the circuitry of the brain have revealed separate
locations for two major life principles: one relating to survival of
the individual, located in the temporal lobe, and the other relating
to the preservation of the species, located in a midline region of
the forebrain. At present, regions of sexual representation in the

■<C£j8

- 10 -

forebrain are "being studied. Important advances have "been made
toward identifying brain mechanisms relating to consciousness and
alertness as they are differentially affected by narcotic, psycho-
tomimetic, and tranquilizing agents. A significant new finding
about the action of the thyroid hormone on protein synthesis may
explain many of this hormone's important functions and the mechanism
whereby its lack causes cretinism, a state of mental and physical
retardation.

The Current Status
Despite these developments during the last several years,
the major task still lies ahead. Although resident mental hospital
populations declined during 1959 for the fourth consecutive year,
there still were over half a million patients in the 277 public
mental hospitals in the United States at the end of fiscal year 1959-
The annual tax bill for the care and treatment of the mentally ill
still exceeds $3 billion. And though the number of discharges from
mental hospitals is increasing, so is the total number of admissions.
Admissions to mental hospitals increased by 6.5 percent between 195^
and 1959; and this was on top of a 7-7 percent increase the year
before. Recent revaluations of the mental health manpower situation,
show that although the number of trained persons has increased
significantly, the demands for such personnel have increased at an
even greater rate. Much valuable progress is being made in the wide-
spread areas of mental health research, many answers are still unknown,
and true preventive work in mental health is still in its developmental
stage .

«Sf

- 11 -

Pr ogress in the Past Year
Important progress x*as made during the past year in the
various Institute programs * There were new research findings,
increases in mental health training, expanded community services
activities, and significant advances in special areas such as
psychopharmacology, juvenile delinquency, and alcoholism. Each of
the Institute's major programs has included both activities designed
to develop more effective methods of treating mental and emotional
disorders and activities which attempt to find ways of preventing
such disorders. Therapy and prevention have been the dual goals in
research, in training, in community services, and in the work on
special mental health problem areas. Basic laboratory and clinical
research in the biological, psychological, and sociological sciences
seeks to develop knowledge which will explain the factors controlling
mental health and mental illness. Clinical studies, applied research,
and special projects and demonstrations aim at developing more effec-
tive ways of treating mental and emotional disorders and of bringing
better and prompter care to all types of individuals who need mental
health services. The Institute supports training for a very broad
range of professional personnel who can contribute to therapeutic
and/or preventive work in the field of mental health. The work in
community services also includes activities designed to develop and
strengthen State and local programs devoted to care and treatment and
programs aimed at building sound mental health.

X>J

- 12 -

Research

Recently, research has suggested that some forms of mental
illness may he related to "biochemical processes in the "brain and
nervous system. Establishing definite causal relationships between
changes in brain functions and the occurrence of mental illness is a
complicated task since the brain is the most complex structural
organization known to man. It is made up of a great many separate
subsystems, each with its own neurophysiological and biochemical
patterns of organization.

One approach to this problem lies in the search for possible
psychotoxic substances that may occur in the blood or urine of
patients suffering from mental illness. Many pitfalls plague this
area of research, however, and all to frequently exciting early
reports of significant biochemical differences between normal and
psychotic persons fail to stand up under adequately controlled repli-
cation. National Institute of Mental Health grantees and scientists
from the Institute's own research programs have contributed important
new knowledge in this field and have demonstrated the importance of
rigorous dietary controls in biochemical studies on mental illness.
Institute scientists engaged in a multidisciplinary program of
biological studies in schizophrenia have spearheaded a growing
awareness of the sources of error in a more critical approach to the
biological factors in schizophrenia. Many of their concepts are
becoming widely used in the prosecution of similar undertaking here

- 13 -

and abroad. For example, the psychiatric, genetic, social, and
medical criteria for the selection of schizophrenic patients in
biological studies of the disease established by Institute scien-
tists have constituted a model for studies elsewhere.

Another major area of research is on the structure of the
brain itself. A large number of Institute grantees are conducting
studies on the behavioral role of some of the brain subsystems. The
functions of various parts of the brain are being mapped with the
aid of new devices which permit electrical and chemical stimulation
to be applied with increasing accuracy to specific parts of the brain.
Institute support has been provided for the first time this year for
a long-term program of combined behavioral, anatomical, and neuro-
physiological studies in "'split -bra in" animals in which the cerebral
interhemispherical connections are interrupted. This technique pro-
vides a unique opportunity for evaluating the extent of transfer of
stored information from one hemisphere of the brain to the other and
for isolating certain brain pathways and mechanisms. It is expected
that this program will contribute significantly to our knowledge of
the underlying mechanisms of memory and learning.

Clinical investigators at the National Institute of Mental
Health are conducting studies of emotional aspects of behavior, and
are using new biochemical methods for the microanalytical assay of
blood hormone concentrates which make it possible to confirm or deny
clinical impressions with more precise measurements . Recent findings

- lis- -
have emphasized the likelihood of some predisposition on the part
of certain individuals to specific psychosomatic dysfunction. Inves-
tigators supported by Institute grants are conducting research on
the specificity of physiological reaction to stress and on the
patterns of autonomic responses in psychosomatic disorders. The
Institute is also supporting several studies on the hereditary
aspects of mental illness. These investigations suggest that
heredity plays an important role in some types of psychosis and in
some forms of mental retardation. However, the genetics of behavior
is still a largely unexplored field, and the hereditary basis of
normal behavior and of specific mental disorders requires much more
exploration.
T raining

As of 1959, programs were being supported for research training
of psychologists and for the interdisciplinary training of psychia-
trists and of biological and social scientists. In I960 support of
research training was broadened to include all four mental health
disciplines => In addition, support for research training in the
biological and social sciences was extended. The greatest proportion
of awards in I960 for research training in the biological
sciences included considerable emphasis on psychopharmacology.
This has been especially appropriate because of the acute shortage
of Qualified research workers in this area.

'•• -VI

-it ic

- 15 -

In September 1958 » "the first official announcements describ-
ing the Institute's psychiatric training program for general
practitioners were issued. Within six months the total funds
allocated for the program were obligated,, Under this program, the
Institute provides support for general practitioners who are taking
psychiatric residency training, and for postgraduate psychiatric
training courses for general practitioners o A total of $2,300,000
will be expended for this purpose in I960. The importance of these
training activities is highlighted by a recent estimate that at
least 90 percent of all psychiatric problems receiving medical atten-
tion are handled in the office of the family physician.

Support was initiated in I960 for the development in medical
schools of training programs leading to the integration of the
behavioral sciences into the education of the modern physician, thus
giving him a broader scientific basis for understanding human behavior.
Research models are needed in the behavioral sciences which will be
as meaningful and strong in their impact on medical education as
those presently available for teaching in existent basic science
departments and in other branches of medicine.

Undergraduate psychiatry grants, awarded since 1950 » have
enabled departments of psychiatry in all major medical schools and
schools of osteopathy to improve and expand their undergraduate instruc-
tion in psychiatry. In a number of medical schools, these funds have
been a major factor in the establishment of new departments of

- 16 -

psychiatry and in the expansion of needed teaching staff. One new
grant of $25,000 to be awarded in i960 brings the total to 88 medical
schools and schools of osteopathy each receiving up to a maximum of
$25,000 for teaching costso

A portion of the funds provided in i960 was used to expand
existing graduate teaching grants in a limited number of nurse
training centers. During the past year, there was also an expansion
of support in both clinical psychology training centers and centers
for research training in fields of psychology relevant to mental
health. A small experimental program of research training for under-
graduate students was initiated in the summer of 1959 to offer extra-
curricular research experience for the early development of research
interests in undergraduate students majoring in psychology.

The Institute now makes grants to 51 of the 56 graduate schools
of social work in the United States. Fifty of the 51 received grants
in psychiatric social work, and 1? of them received grants in school
social work. For the first time, grants were awarded to training
programs in the fields of aging, family and child welfare, correc-
tions, and community planning. This represents the first application
of funds for training social work personnel for work in these preven-
tive mental health programs.

A significant number of behavioral and social scientists are
receiving research training in fields important to mental health
(psychology, psychiatry, sociology, and anthropology) through the

O'l J

- 17 -

research fellowships program. Support is being given to promising
graduate students who desire to devote their lives to a career of
research in mental health, to young scientists who have already
received their basic training and require further more advanced
training, and to mature scientists who desire specialized training
which will assist them in their work on a specific problem. This
program provides an essential reservoir of trained personnel for
work on the many research projects supported by the National Institute
of Mental Health. Many former research fellows are now receiving
grants in support of their studies as independent investigators.
Community Services

State mental health programs continue to expand and develop at
an increasing rate. Technical and professional assistance by Institute
staff and Federal grants-in-aid have proved effective instruments in
stimulating the development of more adequate State programs. Federal,
State, and local funds budgeted by the States for community mental
health services reached a new peak of $6h.Q million in 1959 — a 20 per-
cent increase ($10.8 million) over the previous year. The Federal
grants-in-aid of $4 million in 1959 represented only 6 percent of the
total funds budgeted. About $9 million of the total 1959 funds avail-
able to the States were budgeted for the expansion of clinical and local
mental health services. The remainder of the increased funds was used
to expand State -level staff, research, and training — all areas in which
there is great need to strengthen present programs. Although there has
been a rapid growth in the number of clinics since 19^6, when the Mental

- 18 -
Health Act was passed, lack of such services, particularly in rural areas
throughout the United States, still continues to he a major problem.
State programs received needed help when Federal grants to States were
increased to $5 million in i960.

During April 1959, the Institute held the second of a series of
orientation conferences for State-level personnel. These meetings
provide an opportunity for State people responsible for mental health
program planning to share new ideas, and to discuss present programs and
ways of strengthening and expanding them. Sixty -five representatives
from selected States attended the meeting.

In 1955, the Institute evolved the idea of providing support,
through negotiated contracts, for workshops and conferences held in a
specific State on a particular problem directly related to the develop-
ment of the State mental health program. This Technical Assistance
Projects program has become an effective mechanism for strengthening
community mental health programs, coordinating mental health activities,
and bringing to people working on State problems expert knowledge on
specific subjects. Published reports of these projects are circulated
to all State mental health programs.
Alcoholism

A 5 -year grant in the amount of $1 million has been made to
the North American Association on Alcoholism Programs (an organiza-
tion of alcoholism program administrators in the United States and
Canada) for the purpose of establishing an independent Cooperative
Commission on the Study of Alcoholism. This Commission will reexamine

- 19 -
the whole problem of alcoholism in the United States and Canada and
recommend future policy and action. Up until now only piecemeal,
administratively uncoordinated efforts have been made against alcoholism,
and there has been no single body to review and evaluate what has been
done and to map a plan of action. For the first time, a unified and
impartial approach will be made to this urgent and costly problem.

A special grant was made to the California State Department
of Public Health to develop instruments for measuring the incidence
and prevalence of normal alcohol usage patterns, and to provide
epidemiological information about the nonpathological use of alcoholic
beverages. A western community of 400 families composed of three
ethnic groups is the laboratory for a 5-year project aimed at obtain-
ing information on the entire range of drinking behavior as well as
other data on the mental health of the community. The project will
study the prevalence and variety of patterns of maladjustment among
the three ethnic groups; the extent to which variables in group
attitudes, values, social structure, and other cultural patterns
correlate with differences in the mental health of the groups; and
to what extent any prevalent evidences of maladjustment, including
drinking behavior, can be understood in terms of personality charac-
teristics and in terms of cultural forces.

During 1959 Technical Assistance Projects on alcoholism were
held in 10 States on such subjects as community resources for the
rehabilitation of the alcoholic, alcoholism as a mental health problem
in business and industry, mental health aspects of alcohol education,

- 20 -

and the family-centered approach to alcoholism. The conclusions reached
by these institutes stressed the importance of approaching the subject
of alcoholism on a community basis and affirmed the efficacy of concerted
effort in doing something about the problem^

The Institute, in^cooperation with the Division of Special
Health Services, Bureau of State Services, has started planning for a
series of small working conferences devoted to the general problem of
automobile accidents associated with drinking of alcohol. Each con-
ference will be concerned with a particular aspect of the problem;
e.g., psychological and physiological effects of alochol consumption;
enforcement, detection, and legal aspects; driving-drinking mortality
and morbidity statistics; education and mass motivation; and social-
psychological factors. When this series is completed, the various
findings will be brought before a major national conference scheduled
to be held in the spring of 1961.
Juvenile Delinquency

The National Institute of Mental Health and the Children's
Bureau are preparing, at the request of Congress » a report which
attempts to answer the question: What can and should be done to con-
trol juvenile delinquency? The report will include both substantive
and fiscal proposals for action considered to be necessary and
desirable in attacking the problems of juvenile delinquency in the
United States. Thorough study of the whole problem will bring
valuable information, in addition, about child development, particular-
ly of pathology. The Institute is interested in prevention and treat-
ment of juvenile delinquency, as well as in research in this field and

* 21 -

training of personnel to deal with the problem* Several agencies,
with support from the Institute, have designed community- wide delin-
quency control projects to test the effectiveness of present techniques
and recommended services that appear to hold promise for the prevention
of delinquency. The Institute is already partially supporting such pro-
grams in several urban centers. Recently, large-scale support was given
to initiate a major demonstration project and field experiment for
delinquency control.
Mental Health Project Grants

The Institute's Mental Health Project Grants Program, initiated
in 195? under authority of Title V of P.L. 911, of the 84th Congress,
supports projects aimed at new and improved methods for the care, treat-
ment, and rehabilitation of the mentally ill. During the past 2
years, emphasis has been placed on studies focused on improved
hospital care and treatment, improved administration practices, and
improved community mental health programs. These projects have been
aimed at the development of new concepts and treatment techniques,
better integration of service between the hospital and the community,
a more therapeutic atmosphere within the hospital, better methods of
early detection and prevention, more effective alternatives to
hospitalization when indicated,, and improved rehabilitation services
for discharged patients. Special consideration has been given to
projects aimed at the above purposes when they pertain to critical
problem areas such as alcoholism, aging, juvenile delinquency, mental

- 22 -
retardation, or schizophrenia. Although most of these projects are
still in process, some have progressed far enough to permit preliminary
assessment. In one such project, aimed at establishing and evaluating
an intensive psychosocial treatment program for chronic psychiatric
patients, a therapeutic milieu has been created for patients originally
in a custodial setting. A home-like atmosphere has been introduced;
there is intensive inservice staff training at all echelons, including
both professional and nonprofessional personnel; and a broad program
of patient activities has been introduced. Preliminary indications
are that such measures are effective in the rehabilitation of hereto-
fore "chronic" patients. Definite improvement in employee morale is
also reported. The extension and application of such intensive and
comprehensive measures hold much promise not only for acutely ill
patients but also for chronically ill patients, who for so long have
comprised a major factor in the high costs of public mental hospitals
and who have been a source of much discouragement.
Psychopharmacology

The program of the Institute in psychopharmacology has three
major components:

(1) The evaluation of the clinical efficacy of drugs with
potential utility in the treatment of psychiatric conditions.

(2) The development and assessment of potentially useful
methods for the identification and characterization of
new drugs at the preclinical level.

(3) The elucidation o f the basic mechanisms of action of
known psychoactive drugs.

r^io £•«=">.

;-. ( r f

- 23 -

The Institute's Psychopharmacology Service Center, through
its staff and its special consultants, helps to stimulate research
by working with individual investigators and with small groups of
researchers focusing on special problems that need intensive study.
Psychiatric, pharmacological, psychological, and statistical advisory
services are made available to investigators. The Center also provides
on request, bibliographical material and special technical informa-
tion concerning published and unpublished work in this field. In
addition, it organizes conferences and works with consultants in the
analysis of the current state of research in psychopharmacology, using
these analyses as the basis for its stimulatory activities.

The effectiveness of these efforts to stimulate research is
exemplified by the fact that at the September 1959 meeting of the
American Psychological Association approximately one -third of the
papers directly relevant to psychopharmacology reported work which is
being supported by Institute grants. These papers covered a wide
range of research, much of which has clinical implications. Some
described new or modified techniques which might be used to screen
drugs for behavioral or psychological effects. Others reported
investigations of the effects of specific drugs on the behavior or
psychological test performance of human or animal subjects. Some
dealt with studies of the sites or mechanisms of action of specific
drugs, some with methodological problems. One described experimental
work on a test of hypothalamic excitability that may prove helpful in
psychiatric diagnosis.

- 2^~

Conclusion

To continue the vital work of the Institute and consolidate

the gains made during the past year, the appropriation request for

1961 is a total of $67,563,000. This compares with the appropriation

of $68,090,000 for I960. This allowance for 1961 will provide for the

continuation of I960 program levels in all activities. An adjustment

downward of $3,850,000 reflects the nonrecurring adjustment of project

period starting dates of training grants. An increase of $3,208,000

will be available for additional support of research grants.

The request for 1961 is distributed among program activities

as follows:

Research projects $26,690,000

.Research fellowships 1,996,000

Training grants 22,356,000

State control programs 5,000,000

Research 7,697,000

Review and approval of grants 1,293,000

Training activities 100,000

Professional and technical assistance- 1,926,000

Administration 505,000

Total - $67,563,000

SUMMARY OF OPENING STATEMENT

Director, National Heart Institute

Public Health Service

COMMITTEE ON APPROPRIATIONS
1961 ESTIMATE
fcr
"National Heart Institute"

Mr. Chairman and Members of the Committee:

The year I960 has been one of substantial progress toward
achievement of the program goals of the National Heart Institute.
Expanded activities in our laboratories at Bethesda and those sup-
ported by grants in other institutions have been productive in terms
of research results. Increased funds provided have also favorably
influenced the development of needed research manpower and of com-
munity heart disease programs. Furthermore, emphasis has been given
to a number of areas of particular interest, such as analysis of fats
in atherosclerosis research, blood coagulation and clot dissolution,
epidemiological studies, drug development and evaluation, and primate
research centers.

Diseases of the heart and blood vessels took 893,489 lives
in 1958. Death rates for some types of cardiovascular disease,
including rheumatic heart disease and hypertension, have decreased
in the past nine years. The rate for arteriosclerotic heart disease,
however, the component which includes coronary disease or "heart
attacks", climbed over 30 percent from 201 per 100,000 population
in 1949 to 266 in 1958.

- 2 -

Important advances continued to be made against the major
types of heart disease. In atherosclerosis, understanding of the
hormones, protein structures, enzymes, and physiologic mechanisms
involved in storage, transport and utilization of fatty substances
was increased during the year. Attention has also centered on
dietary and other means of lowering blood cholesterol as possible
measures for controlling the disease, and the role of stress as a
factor in elevating blood cholesterol levels has been further
elucidated.

In the field of hypertension, the development of drugs for
reducing high blood pressure has progressed. Knowledge that certain
enzyme inhibitors can be used for lowering blood pressure has opened
a new area of research which appears most promising. In cerebro-
vascular disease, the application of X-ray methods for visualizing
the blood supply to the brain has shown that flow is often blocked
in surgically accessible blood vessels in the upper chest and neck.
A large-scale study is under way for the selection of operable
patients in the hope that the progress of occlusive disease leading
to strokes may be averted in such individuals.

An important development in the control and prevention of
rheumatic fever was the recent validation of the fluorescent anti-
body technique in field tests. The technique, which makes possible
rapid identification of Group A beta hemolytic streptococci, may

- 3 -
well lead to ultimate eradication of rheumatic fever and rheumatic
heart disease. Through heart disease control activities, the
widest possible application of the new technique is being fostered
by providing training and furnishing requisite equipment to the
States.

The appropriation request for 1961 is a total of $63,162,000
as compared with the appropriation of $62,237,000 for 1960. This
allowance for 1961 will provide for the continuation of 1960 program
levels in all activities and will permit some increase in grants
for research projects and minor increases in the direct research
activities of the Heart Institute. This request for 1961 is
distributed among program activities as follows:
Grants :

Research projects $37,115,000

Research fellowships 2,663,000

Training 8,588,000

State control programs 3,125,000

Direct operations :

Research 8,359,000

Review and approval of grants ....... 1,152,000

Training activities 185,000

Professional and technical assistance 1,729,000

Administration 246,000

Total 63,162,000

OPENING STATEMENT

Director, National Heart Institute

Public Health Service

COMMITTEE ON APPROPRIATIONS
1961 ESTIMATE
for
"National Heart Institute"

Mr. Chairman and Members of the Committee:

This year has been one of substantial progress toward achievement of
the program goals of the National Heart Institute, Advances have been
registered along every front from basic laboratory work to practical
clinical application.

The past few years have seen many important developments which, in
themselves, provide evidence of the fruitfulness of the Institute's approach
to the cardiovascular diseases. Some of these have, in addition, culminated
in program efforts which appear to offer much future promise c In the Heart
Institute's intramural research, for example, the development of a sensitive
detection device for gas chromatography is enabling much research relating
to fats and atherosclerosis that was not previously possible. Similarly,
basic investigations on serotonin and norepinephrine, leading to the
knowledge that inhibition of the enzyme, monoamine oxidase, can produce
marked lowering of blood pressure, has opened a new area of research in
hypertension. The capacity use of patient beds allotted to the Heart Insti-
tute in the Clinical Center is another instance of research program
development, permitting a chain of integrated studies throughout the range of
medical investigation from laboratory exploration to clinical testing in

- 2 -
humans. In each of the other major areas of the Institute's total program —
support of research, training, and application of knowledge—correspondingly
significant developments have occurred. This statement will present for
the Committee some of the recent achievements and activities in the
strengthened effort against heart and blood vessel diseases.

PRESENT STATUS OF HEART DISEASE

Diseases of the cardiovascular system took 893,489 lives in 1958.
Arteriosclerotic heart disease, the component which includes coronary
disease or "heart attacks", accounted for over half of the total--461,373
deaths. Cerebrovascular lesions, including strokes and other blood vessel
disease in the brain, was second in numerical importance with 190,758 deaths.
Hypertension, with or without accompanying heart disease, accounted for
87,732. The rank order of mortality for other sizable components of the
cardiovascular category was: non-rheumatic chronic endocarditis and other
heart muscle degeneration- -58, 595; general arteriosclerosis--34,443; and
rheumatic fever and rheumatic heart disease-- 18, 796.

The death rate for diseases of the cardiovascular system has increased
somewhat in the last nine years, from 485 per 100,000 population in 1949 to
516 in 1958. It is revealing in this connection, however, to compare the
rates for the various components of the cardiovascular category for these
two years. Death rates for rheumatic fever and rheumatic heart disease, for
non-rheumatic endocarditis and other myocardial degeneration, and for hyper-
tension—all showed declines in 1958 from 1949. The rates for general
arteriosclerosis remained about the same. But the rates for the two largest

- 3 -
componeiits--arteriosclerotic heart disease and cerebrovascular lesions- -were
both higher for 1958 than for 1949 . The death rate for arteriosclerotic
heart disease climbed over 30 percent from 201 per 100,000 population in 1949
to 266 in 1958.

HEART INSTITUTE RESEARCH

The National Heart Institute is engaged in research directed at
understanding the life processes in which cardiovascular disease is rooted
as well as research aimed at controlling these disorders. Biological science
has the same kind of relationship to clinical medicine and its devices for
healing that physical science has to engineering and its devices for
construction and destruction- -the relationship of any science to the
technology it supports. The technology is dependent upon and inseparable
from its supporting science.

Although the Heart Institute exists to gain control of cardiovascular
disease, and conventional reporting practices dictate communication to the
non-scientific public in terms of this vitally useful goal, scientific
research which is concerned only with knowledge is the necessary means to
that useful goal. There must be an awareness of the means as well as the
ends for a sound image of the way progress in medical research is made.

Our hope of understanding the causes of the great cardiovascular
diseases that are our chief cause of death rests upon gaining insight into
the basic biochemical and physiological processes among which these disorders
arise. Our understanding of the causes of cardiovascular disease is limited
by our limited understanding of these basic phenomena.

- 4 -
One of the primary objectives of the intramural research program has
therefore been to gain a more effective understanding of these phenomena.
Important progress has been made during 1959 in this purely scientific
(knowledge- seeking) effort. Pursued freely in cooperation with the practi-
cal and humanitarian interests of the physician in disease, augmented by a
normal spirit of competition, curiosity concerning basic phenomena is
exploited for the conquest of disease. The research environment of the Heart
Institute is maintained in accordance with this concept.

Arteriosclerosis

Because of its high degree of association with abnormalities of blood
fats, and because it is characterized by the excessive deposition of fatty
substances in blood vessel walls, arteriosclerosis seems to be due largely
to abnormal disposition of fats in the body. The progress which has been
made in intramural research during 1959 has been largely in improved under-
standing of the hormones, protein structures, enzymes, and physiologic
mechanisms that are involved in the storage, transport, and utilization of
fatty substances.

Earlier studies at this Institute led to the realization that the well-
known hormone, adrenalin, is involved in the normal mobilization of stored
fat into the blood to sustain life processes during emergencies. The exten-
sion of these studies during 1959 has shown that excess adrenalin, acting in
concert with cortisone, another hormone from the adrenal gland, can cause a
striking increase in the cholesterol-bearing lipoproteins in the blood.
Adrenalin is the chemical through which emotional excitement is normally

- 5 -
expressed in the tissues (the "chemical analog of emotional stress"), and
both adrenalin and cortisone secretion increase in subjects exposed to
physical and emotional stresses. The rise in blood cholesterol that occurs
in response to these hormones is comparable to the rise in blood cholesterol
seen in men exposed to various occupational stresses. The discovery of a
pattern of "stress" hormones that seems to link nervous tension with fat
transport and utilization suggests a plausible and useful concept of how the
body may translate high tension living into high blood cholesterol.

Several methods have been developed for lowering the blood cholesterol
level by restriction and appropriate supplementation of the diet or by the
administration of certain drugs which inhibit the synthesis of cholesterol in
the body. It is important } however, to realize that the exact mechanism by
which the blood cholesterol is lowered is not understood in any of these
instances, and it may be that the lowering of the blood cholesterol by such
abnormal means may be more harmful than beneficial. For instance, in the
case of two drugs which had been shown to lower blood cholesterol and which
had advanced to the stage of trial in man, the blood cholesterol was lowered
but the lowering was associated with accumulation in the blood of abnormal
substances closely related to cholesterol. One of these drugs has been
recently and widely introduced for clinical trial as an experimental drug for
reducing the blood cholesterol. Studies in the Heart Institute have shown that
although the blood cholesterol is, indeed, lowered, the immediate chemical
precursor of cholesterol, normally absent from the blood, appears in appreciable
amounts. Whether this substance is any more or less likely than cholesterol

- 6 -
to produce the artery-clogging lesions of atherosclerosis is uncertain, and
the possible other effects of this abnormal sterol remain to be determined.
Such findings, however, point up a major question with regard to lowering of
blood cholesterol--should an attempt be made to lower the level by a direct
approach or is it essential to learn why the blood cholesterol is high in
those prone to develop atherosclerosis and direct the attack at the underlying
cause? The further problems which may be produced by lowering the blood
cholesterol remain to be determined, but certainly the answers lie in a more
complete understanding of the many functions of cholesterol in the body--
especially its role in the intricate protein vehicles (the lipoproteins) that
carry the fatty acid energy of food to storage or consumption in the tissues,
its role in the maintenance of cell structure and its behavior as a precursor
for vital hormones.

The relatively recent finding that the transport of saturated fatty
acids, such as those of animal origin, seems to require the mobilization of
more cholesterol than the transport of the unsaturated ones of vegetable
origin has directed attention to the problem of the specific fatty acid
composition of food and body fats. The differentiation among different fats
with regard to the identity of their fatty acids has hitherto received
relatively little attention because of a lack of analytical tools for
separating and quantifying them as well as a failure to appreciate the
possible importance of such differentiation. Each fat molecule contains
three fatty acids, each of which has as its backbone a long chain of carbon
atoms . The carbon chain may vary in length from 10 to 12 atoms to more than

- 7 -
twice that number and may contain "double bonds" (points of unsaturation)
at as many as three points. There are therefore many combinations and
permutations and the identity of a fat can be clear only when its fatty
acid composition is known. The recent introduction of an instrument known
as the gas chromatograph brought within the realm of feasibility the
separation and measurement of the exact composition of fats. The method
has required considerable adaptation which has been achieved through the
cooperative efforts of a number of groups and to which teams in the Heart
Institute have made important contributions. Chemists in the Laboratory of
the Chemistry of Natural Products have made technical advances in the
procedures and materials used for the fractionation of several types of fats
of medical interest. The methods for measuring infinitesimal quantities of
materials derived from the separation process have been improved and
increased some tenfold in sensitivity by the design , in the NHI Laboratory
of Technical Development, of a radio frequency discharge detector capable of
accurately quantifying amounts measured in billionths of an ounce. The
application of these techniques will make it possible to study the members of
the heterogeneous class of fats as individual substances, which may well
behave in quite individual fashion.

Hypertension

In the Heart Institute, as elsewhere, the research on hypertension
has two aims. One is to clarify the mechanisms by which blood pressure is
regulated and the nature of the disturbances of this regulation in hyper-
tension. The other is the direct development of drugs and other devices for

- 8 -
lowering high blood pressure and reducing its threat to the individual who
has developed symptoms of hypertension.

Although in recent years there have been considerable improvements in
the drug treatment of hypertension with an appreciable brightening of the
outlook for the average patient with the disease, the fundamental causes
of this widespread disease are largely unknown. Because hypertension of
any degree increases the risk of arteriosclerosis and coronary artery
disease, there is, beyond the continued improvement in the effectiveness
of drugs, a real need for preventive as well as ameliorative measures.
Treatment with any drug requires that the physician balance against the
anticipated benefits the possibility of undesirable effects. In the
management of hypertension the fact that most of the available drugs fall
far short of ideal means that many patients are considered not sufficiently
ill to require drug therapy. As the drugs are improved not only will the
more severely hypertensive individuals be more effectively treated, but more
of those patients v.ith lesser elevations of blood pressure can be expected
to come under control before there is further advance in the disturbance.

Although there is always the possibility of turning up a useful drug
through the random testing of chemical compounds for their effects on the
condition or variable to be treated, such procedures have an extremely low
efficiency. Much more is to be expected s when the field can be narrowed,
through an understanding of specific mechanisms, to compounds of a specific
chemical type and aimed at affecting a specific biochemical mechanism for
which the requirements can be determined. In this regard, the discovery

- 9 -
of one series after another of drugs which lower blood pressure has been
largely dependent upon our understanding of the nervous, hormonal and
muscular components in the maintenance of blood pressure. It is illustrative
of the importance of this more rational approach that two promising groups
of compounds, recently developed in considerable measure through the efforts
of Heart Institute investigators, have, under the usual conditions for
screening, no blood pressure lowering activity in animal tests. Yet both
have important effects in patients with hypertension.

Most of the currently used anti-hypertensive drugs exert their
effects on regulatory systems which had been recognized and at least
partially elucidated before the possibility of manipulating them for the
management of hypertension had even been considered. The control of the
caliber of blood vessels by the activities of the autonomic nervous system
has been known for many years and the surgical interruption of these nervous
pathways by the procedure known as sympathectomy was one of the earliest
procedures aimed at the treatment of hypertension. It then became possible
to accomplish the same effect with drugs which paralyze the autonomic
nervous system. The chemical structure necessary for such activity is now
well known and a number of such substances are in general use. The many
undesirable effects of paralyzing the sympathetic nervous pathways has
prompted a continued search for drugs with more specific effects. Since
the autonomic nervous system includes two subdivisions, the sympathetic and
parasympathetic, and since only the sympathetic is involved in maintaining
the blood pressure, it was highly significant that the impulses in the

- 10 -
sympathetic system are transferred to their target organs by the release of
the hormone noradrenalin. Thus, by impairing the synthesis or destruction of
this hormone, it might be possible to modify the transmission of sympathetic
nervous activity. Again falling back on basic information acquired earlier,
in considerable part through the efforts of Heart Institute biochemists, it
was possible to consider the various chemical steps at which the synthesis
or destruction of noradrenalin might be inhibited. Trial of such compounds
has shown that they, indeed, do lower the blood pressure in hypertension.
One group is that of the monoamine oxidase inhibitors, which interfere with
the enzyme responsible for destroying noradrenalin and other chemically-
related substances at nerve endings and which have gained wide use in
psychiatry as "psychic energizers." Trial of one of these compounds in
hypertension revealed a very high degree of activity and freedom from the
usual side effects of autonomic nervous system blockers. Unfortunately the
appearance of another serious side effect-~impairment of vision-=has elimi-
nated this particular compound from further use. But the knowledge that
such inhibitors can be used for lowering blood pressure makes possible the
synthesis of a variety of compounds with similar inhibitory activity which may
not have this side effect.

Meanwhile studies are continuing in the quest of other drugs which
modify the production in the body of amines, the family of highly active
substances of which adrenalin is a member.

Congestive Heart Failure

Congestive heart failure is the group of disturbances which result

- 11 -

when the heart is no longer able to meet the demands placed upon it for
maintaining an adequate circulation to the tissues. It is the end result
common to all of those cardiovascular diseases which place an increased load
upon the heart. For many years, the fundamental steps in the response of the
heart to load have been formulated in accord with Starling's Law of the
Heart. This law describes the behavior of the heart as its filling
pressure is modified--stating that, as filling pressure is increased, the
heart muscle fibers lengthen, and as the fibers lengthen, the heart's out-
put with each beat increases. However, as the lengthening of the fibers
increases a point of diminishing returns is reached beyond which further
lengthening leads to decreases rather than increases in output . This turning
point where the relationship between filling pressure and output becomes
inverted represents the onset of heart failure.

Findings in the Laboratory of Cardiovascular Physiology during 1959
modify and greatly extend Starling's classic Law of the Heart. These
physiological studies were aimed at learning how the performance of the
heart as a pump is changed to meet the demands of the tissues for blood and
how these demands are communicated to the heart.

These studies have provided a unified concept of the basic control of
cardiac output by the autonomic nervous system overlying and integrated
with the intrinsic responses of the heart muscle described by Starling's Law.
The experiments have shown that impulses from the sympathetic ("adrenalin-
transmitting") part of the autonomic system can greatly increase heart work
even when filling pressure and fiber length remain unchanged. Changes in

- 12 -
pressure in certain of the major blood vessels of the circulation are
monitored by nervous receptors, and signals are transmitted to the heart via
the sympathetic nerves. In response to such signals the contractile, pumping
force of the heart muscle and along with it the heart's output of blood are
increased or decreased so as to keep pressure and flow to vital organs at the
desired level. The relationship between filling pressure and output
described by Starling's Law is thus adjusted upward or downward through
automatic nervous controls in accord with the needs of the body. Thus, in
considering the factors that contribute to the regulation of heart output
(and that might usefully be controlled in heart disease and failure)
therapeutics will have another important component—sympathetic nervous
activity and its equivalent, adrenalin release--to manipulate.

Another important line of scientific discovery has to do with the
mechanisms by which the balance of sodium and potassium ions is maintained
across cell membranes. This balance governs the fluid volume not only of
the individual cell, but, through its operation in the kidney, controls the
volume of the blood and the spaces between cells. The contraction of
muscle, the conduction of nerve impulse--in fact the life of every cell--
depends on the performance of poorly understood mechanisms by which sodium
and potassium ions are transported across cell membranes. Only in the last
few years has it been recognized that the action of digitalis in modifying
heart action, used empirically in treatment for several hundred years, is
due to its effect on these ion-transporting mechanisms.

Some of these ion transport mechanisms, particularly in the kidney,
are controlled by hormones. Aldosterone, a steroid from the cortex of the

- 13 -
adrenal glands, causes the kidneys to withhold sodium, and consequently
water, from the urine. Without this salt-retaining hormonal activity,
excessive urinary loss of salt and water, and eventually death, result. But
in persons with the edema of heart, kidney and liver disease, an excess of
aldosterone is secreted. Institute research therefore includes a major
effort directed at studying the mechanisms that regulate, aldosterone
secretion from the adrenal cortex.

During 1959, evidence was obtained by NIH physiologists that still
another hormone appears in the blood to stimulate aldosterone secretion
during congestive heart failure. Further steps are being taken to determine
the nature and source of this new hormone. At present it seems most probably
to originate in a brain structure--possibly closely related to the pituitary
gland. Each link, exposed by scientific inquiry, in the chain of events
leading to abnormal sodium retention exposes another point for clinical
attack on the problem of cardiac edema.

RESEARCH GRANTS

Methods of treatment and means of prevention of cardiovascular
diseases have been improved during the past year through research supported
by grants, from the National Heart Institute. Some of these accomplishments,
and the avenues of investigation being used, are described below.

Arteriosclerosis

Research workers in the field of arteriosclerosis, and coronary heart
disease in particular, are pursuing the answers to such cogent questions

- 14 -
as: What dietary recommendations can the medical profession make to patients
who have coronary disease? Can a practical food pattern be developed for the
whole population that will be effective in reducing serum cholesterol levels
and maintaining them at lowered levels to decrease the risk of coronary heart
disease? What is the effect of "stress" on the development of the disease?

It is generally agreed that blood lipids are deeply implicated in
atherosclerosis. Studies are being made of the hows and whys of their action
on arteries. A feeding experiment in man indicates that two highly unsaturated
dietary fats--one poor in essential fatty acids and sterols and the other rich
in these two factors--have similar effects on human serum lipid levels,
implying that the unsaturation of dietary fat rather than its content of
essential fatty acids and sterols is important in lowering serum lipids.
Another study of patients maintained on a fat-free diet long enough to
reduce plasma lipid levels to a plateau shows that the further lowering of
plasma lipids is due to the addition of unsaturated fat to the diet rather
than to the subtraction of other materials.

Big strides are being made in development of technical devices and
procedures for the separation and analysis of biologically important fatty
acids. For example, in gas chromatography, by which fats may be analyzed
with unprecedented sensitivity, capillary columns are found to possess an
efficiency exceeding that of conventional columns by several hundred percent.
Availability of such methods should bring forth new information on the role
of these fatty acids in health and disease.

The stress imposed upon man in his quest for economic or social
"success" may be playing havoc with his health. A study of a group of

- 15 -
patients with clinical evidence of coronary artery disease suggests that
circumstances interpreted by the patients as stressful elevated the serum
cholesterol level, when diet and exercise were held constant.

A variety of drugs has evolved for use in arteriosclerotic disease,
but their value in man is not yet established. Soy phosphatides produce
promising results in atheromatous rabbits. A pituitary hormone appears to
stimulate mobilization of fat from adipose tissue. The quest for drugs which
will lower serum cholesterol is engaging the attention of many investigators.
Use of nicotinic acid for this purpose has produced conflicting results, and
additional controlled studies are indicated. This substance is also reported
to promote fibrinolytic activity and is being studied for use in the therapy
of thrombo- embolic diseases. Consistent lowering of serum cholesterol levels
following oral administration of neomycin--an antibiotic--is reported.

Hypertension

Although elevation of arterial blood pressure is the basic attribute
of all forms of hypertension, the etiology of the various clinical types
remains uncertain. "Essential" hypertension and the hypertension that results
from certain kidney diseases, for example, may be unrelated so far as causation
is concerned. On the other hand, it is possible that such secondary
hypertension tends to occur chiefly in persons who are highly susceptible
to the "essential" type of hypertension. Studies are underway to clarify
these points. One in particular is aimed at ascertaining the occurrence of
hypertension among relatives of known hypertensives, to study the

- 16 -
physiological s socio-economic, and environmental characteristics of
individuals in whom hypertension has or has not developed, and ultimately to
determine the effect of familial factors which will throw some light on the
comparative roles of inherited and acquired factors in the pathogenesis of
hypertension.

Disability and death due to hypertension are often more closely linked
to atherosclerosis than to an elevation of arterial pressure per se. The
experimental production of hypertension, the effects of dietary abnormalities,
kidney removal, and the use of kidney transplants in animals are methods
being used to study the relationship between increases of blood pressure and
the tendency to arteriosclerosis.

A host of drugs for the alleviation of high blood pressure are being
evaluated for clinical use. Their mechanisms and sites of action are being
determined in animals by intricate techniques whereby central and peripheral
activity can be distinguished, prior to therapeutic use in patients.

Rheumatic Fever and Rheumatic Heart Disease

Investigations into the chain of events leading to rheumatic fever
have solidified the concept that it usually follows Group A streptococcal
infections. But the mechanisms by which the disease is initiated, the
immunologic processes involved, the roles of environmental factors and of
genetic tendency still beg for clarification. Preliminary data from a study
of streptococcal infection among school children indicate that live
streptococcal bacteria can be cultured from throat swabs of a large
percentage of children during the school year. But the rate of clinically

- 17 -
manifest streptococcal infection has remained relatively low. The
significance of the positive cultures is being intensively studied by
addition of serologic techniques to aid in the diagnosis of streptococcal
illness and to detect the presence of coincident viral respiratory
illnesses, for any viral-bacterial relationships that might bear on the
virulence of streptococcal infection. Various types of drugs are being
evaluated in the prevention and treatment of rheumatic fever „ The use of
intramuscular injections of penicillin in a three-year study of prophylactic
methods proved more effective than either oral penicillin or sulfadiazine.
The current studies will be expanded to verify dose relationships.

A direct approach to the correction of heart damage due to rheumatic
heart disease is the replacement of diseased aortic and mitral valves by
better and safer prosthetic ones with moving leaflets. But the problems of
adequate position and anchorage of artificial valves remain troublesome.

Surgery

In addition to the advances in surgery cited elsewhere, there is an
active search for better methods of arresting and reviving the heart in
conjunction with open heart surgery, such as the use of various combinations
of drugs, perfusion of the heart with oxygenated and decalcified blood, or
perfusion with cooled blood. Recent findings indicate that the inclusion
of devices for cooling body tissues (hypothermia) extends the time the
surgeon has to work within the heart beyond the periods allowed by cardiac
arrest or extracorporeal circulation alone. The requirement for large
volumes of blood during open heart surgery may be reduced as a result of

- 18 -
the experimental finding that perfusion of only a few vital organs rather
than the entire body is sufficient to permit complete recovery after
circulatory arrest even for periods longer than an hour. Particularly
encouraging in the field of tissue and organ transplantation is the
apparently successful transplantation of a kidney between fraternal (not
identical) twins. This constitutes a major advance in terms of the
forbidding problem of the "host rejection" response to genetically different
tissues.

Cerebrovascular Disease

The application of X-ray methods for visualizing the blood supply
to the brain in cerebrovascular disease has shown a high frequency of blocked
flow in such surgically accessible vessels as the arteries in the upper
chest and neck. A large scale study is under way for the selection of
operable patients in the hope of averting in such individuals the progress
of occlusive disease that may lead to strokes. Investigators are also seeking
a means to prevent the thrombosis of small blood vessels in the skull
following surgery, without the use of hazardous anticoagulants. If this is
successful, it may have application to other small blood vessels of the body
as well, such as the coronary arteries. Nutritional factors are being studied
for their effect on cerebral function as they are for their effect on
arteriosc lerosis .

- 19 -
DEVELOPMENTS IN SPECIAL AREAS
Epidemiology

Because of the multitude of factors which may be related to the
development and course of cardiovascular disease, an approach which studies
the various factors as they naturally occur in population groups offers
unique promise. Several factors in our mode of life are suspect, including
mental stress, physical activity, smoking habits, and diet. These are not
easily measured, and associations with disease do not necessarily indicate
cause and effect relationships.

Studies are being done among unique racial groups, with similar
ethnic origin, cultural background, dietary habits and geographic location,
to determine any possible correlation with the incidence of cardiovascular
disease. One seven-year study on 1800 men to determine the incidence of
coronary heart disease in relation to various biological and social factors
indicates that among white males significant differences occur according to
relative weight, blood pressure levels, serum cholesterol levels and family
history of heart disease. No differences in incidence were observed according
to physical activity of the job class (professional, clerical, unskilled
laborer), or to economic status. Another study in progress, on the
epidemiology of congenital heart disease, is pursuing various lines; the
relationship to meteoro logic conditions, radiologic fall-out, pregnancy
histories, blood types of children and mothers, virus content of serum and
heart tissue, race, ethnic origin, income, education and housing.

- 20 -

Blood Coagulation aid Thrombolysis

The clinical problems presented by blood coagulation disturbances
are frequent, challenging and extensive, including the life-long difficulties
of the hemophiliac (bleeder);, gangrenous states in the limbs of the body due
to obstruction of blood vessels, severe paralytic strokes caused by cerebro-
vascular occlusion and sudden death due to coronary thrombosis or pulmonary
embolism. In studies on bleeding disorders due to the decreased amount of
a clotting factor in the blood 9 attempts are being made to isolate the
necessary factor from sources of normal blood plasma and to test its ability
to remedy the defect. The coagulation disturbances associated with arterio-
sclerosis are the subject of considerable research activity in order to
elucidate the factors that increase blood coagulability and impair clot
dissolution and also to develop means of preventing or counteracting these
disturbances. A system recently devised for observing coagulation in
flowing human blood should make further important studies possible. In the
area of anticoagulant drugs, the definitive characterization of an anti-
thrombin isolated from blood now seems possible. Several substances under
study are reported to have potential for counteracting the danger which
might result from excessive anticoagulant levels in the blood.

In addition to these studies concerning the prevention of clotting,
research is actively continuing on the factors involved in thrombolysis, the
dissolution of clots. For example, investigators are attempting to isolate
thrombolytic agents from natural sources such as soil fungi. Plasmin, an
enzyme normally occurring in blood, has been used to dissolve blood clots

- 21 -
experimentally produced in the coronary arteries of test animals. New
knowledge is also being gained about a number of substances, such as strep-
tokinase, that promote clot lysis by increasing the production of active
plasmin in the body. The development of a practical method for the use of
streptokinase on patients with occlusive blood vessel clots is under
investigation.

Drug Research

In the search for improved methods for the treatment of cardiovascular
diseases, research effort will focus on the evaluation of new drugs as well
as the testing of known pharmaceuticals under new experimental and clinical
conditions. In addition to the studies on drugs discussed in relation to
arteriosclerosis, other workers in this field are investigating the use of
hormones such as a synthetic compound related to estrogen that decreases
serum cholesterol and has little or no feminizing power in males, the
value of purified blood components in regulating the formation and lysis of
clots that can occlude blood vessels, and in connection with arterial
surgery, the identification of various chemicals that can adhere to the
inner surface of the arterial wall and minimize clot formation.

Clinical trials of a new drug, guanethidine, indicate its ability to
reduce blood pressure in renal and essential hypertension without the side
effects accompanying other commonly used agents. Other advances in cardio-
vascular drug research that show promise include a compound that may be
clinically useful in treating disturbances in the rhythmical contractions

- 22 -
of the heart and the isolation and testing of plant substances of potential
value for patients with heart failure.

Progress is being made by the Heart Institute in developing a broad
program of drug development. Contacts with the pharmaceutical industry as
a whole were initiated through the Pharmaceutical Manufacturers Association,
a national organization whose medical section has established a Sub-committee
on Cardiovascular Agents. Partly through the work of the Sub-committee and
partly through the initiative of individual firms, direct relationships
have been developed between the Heart Institute and at least 20 pharmaceutical
houses. A National Heart Institute sponsored meeting on standards and
standardization of methods needed for the orderly development of new cardio-
vascular drugs was held in January of this year. More than a dozen
pharmaceutical firms were represented at this conference.

Primate Centers

The need for national facilities for cardiovascular research on sub-
human primates has been of major concern. Provision by the Congress of funds
for this purpose has enabled steps to be taken toward the establishment of
two centers. Thirteen possible sites in various parts of the country were
visited by a Special committee of the National Advisory Heart Council and a
number of these were judged to have sufficient local interest and center
possibilities. Several applications have since been received, which are
being reviewed by the National Advisory Committee on Primates in the Division
of Research Grants prior to final review by the National Advisory Heart
Council in March 1960.

- 23 -
International Activities

A small number of research grants have been made to investigators to
other countries o Also s this year the Heart Institute awarded its first
training grant to a foreign scientist- -A Danish world authority on ion
transport across cell membranes. This training program has attracted many
young researchers from other countries as well as the United States.

The support of conferences , both national and international, on
matters of significance to cardiovascular disease has continued and
broadened. An international meeting in Switzerland attended by 85
specialists on blood coagulation dealt with new clotting factors--a matter
of increasing importance to patients threatened with the formation of
clots in their blood vessels and to physicians who wish to treat these people
effectively with anticoagulants. In connection with this conference 9
scientists from 16 countries agreed on one new item to be added to their
existing list of eight "accepted" clotting factors and agreed on symbolic
names for all nine. This represents progress, as these agreements tend
to increase effective communication among scientists independent of language
differences, and will speed up the application of new knowledge by physicians
Grant-supported conferences in this country have dealt with blood platelets
(another aspect of clotting), control exercised on the cardiovascular system
by the central nervous system, and the epidemiology of the cardiorespiratory
diseases. Arrangements were made for leading foreign scientists to parti-
cipate in all of these.

- 24 -
TRAINING

The National Heart Institute now supports over 250 training programs,
with nearly all medical schools participating. They range from intensive
programs in such fields as lipid chemistry technology and cardiac surgical
research to broad inter-disciplinary training in clinical investigation.
Noteworthy, as a result of the increased Congressional appropriation this
year, has been the development of mu It i- departmental programs where several
laboratories with related research goals pool their training resources to
offer broadly diversified, carefully structured research training oppor-
tunity. We expect that more programs of this type will be developed in
the coming year, especially programs which join preclinical departments
(or even components of other colleges such as electrical engineering
departments or biology departments) with clinical departments in order more
rapidly and authoritatively to bring the research technologies of basic
sciences into clinical cardiovascular research.

Two other programs where much needed further expansion has become
possible as a result of the increased funds for training this year are

(1) training investigators in the exacting methods of drug evaluation and

(2) development of training in areas such as medical electronics, compara-
tive cardiology, medical genetics, and others where special needs are
apparent .

Further, as a pilot program it is planned to select certain
academically oriented and otherwise qualified hospitals in large communitie s
where there are no medical schools, and develop training activities which

- 25 -
will encourage the growth of both basic and applied clinical research in the
hospitals. This program has three aims; (1) to increase the number of loci
of research in the country, (2) to improve the scientific and academic
atmosphere of these institutions so that they may become nuclei from which
medical schools or other graduate medical educational institutions may in
time develop, and (3) to bring medical research closer to the practicing
physician,,

HEART DISEASE CONTROL

The heart disease control program provides technical assistance to
the States in the application of existing and newly developed knowledge of
the cardiovascular diseases. The increase in funds appropriated for the
current year has made it possible to increase the number of medical officers
and others assigned to State, county and local health departments and
selected clinical groups, An additional 29 medical and nurse officers have
been assigned, bringing the total to 48, In some instances, the increase
makes possible the formation of professional teams to strike at vital
heart disease control problems facing the communities to which officers
are assigned; in others, it means the addition of facilities to test n*w
findings and to put to use proved techniques from the laboratories . Some
officers have assisted in establishing entirely new community programs
while others have helped the expansion of existing programs by the inclusion
of important new projects,

A most dramatic development in the control and prevention of rheumatic
fever was the validation of the fluorescent antibody technique in field

- 26 -
tests carried out in cooperation with the Communicable Disease Center and
several State health departments. This technique, which makes possible rapid
identification of Group A beta hemolytic streptococci, may well lead to the
ultimate eradication of rheumatic fever and rheumatic heart disease* The
heart disease control program is now seeking to foster the widest possible
application of this new technique by providing training for State laboratory
technicians and furnishing States with the requisite equipment. Nearly
thirty states will have the equipment and trained personnel by February 1960,
The program is also seeking means for (1) making training in the technique
available to non- governmental laboratory personnel (2) insuring an adequate
supply of the critical reagent, (3) providing professional and lay informa-
tion on the technique, and (4) implementing prevention programs at the local
level.

The control program has contributed to the total national effort in
developmental and applied research in several ways. There are indications
that new, striking diagnostic aids can be developed which will significantly
reduce the demands on the physician's time as well as make life-saving
measures more readily available to the patient. An instrumentation group has
been formed in the program to provide national leadership in this area. A
study of the relationship of emotional stress to serum cholesterol levels
has been completed, showing that a significant increase in mean value for
serum cholesterol accompanies emotional stress. A survey of obesity patterns
over a 20=year period showed that overweight children tend to become over-
weight adults, and that it is difficult to change adult eating patterns. The

- 27 -
study suggests that measures to curb obesity should be undertaken in
childhood if obesity control is to be successful.

Now in its fifth year is a study of rheumatic fever and rheumatic
heart disease among college freshmen which is being conducted in cooperation
with the American College Health Association. In the field of congenital
heart disease, a study of the heart sounds of 40,000 school children was
begun last year. Thus far, about 14,000 individual recordings have been made
and are being studied by pediatricians and cardiologists for possible heart
defects. The significance of "functional murmurs" found in children 20 years
ago has been evaluated by recent re- examination. Preliminary results
largely support the current medical opinion that such murmurs are not
pathologically significant.

SUMMARY

The past year has been one of the most productive since the National
Heart Institute was established. The expanded activities in our own
laboratories and those supported by grants in other institutions have been
rewarding in terms of research results. The increased funds appropriated
by the Congress have also favorably influenced the development of needed
research manpower and of community heart disease programs. Because of this
progress, the outlook for those with cardiovascular disease continues to
improve .

In conclusion, Mr. Chairman, the appropriation request for 1961 is
a total of $63,162,000 as compared with the appropriation of $62,237,000
for 1960. This allowance for 1961 will provide for the continuation of

- 28 -
1960 program levels in all activities and will permit some increase in
grants for research projects and minor increases in the direct research
activities of this institute. This request for 1961 is distributed among
program activities as follows:
Grants ;

Research projects $37, 115,000

Research fellowships 2,663,000

Training 8,588,000

State control programs 3,125,000

Direct operation s;

Research .,,..,,,..*,,.,«,.».... 8, 359,000

Review and approval of grants ,»*.....,.» 1,152,000

Training activities ...............*,.,., 185,000

Professional and technical assistance , ... 1,729,000

Administration 246,000

Total 63,162,000

SUMMARY OF OPENING STATEMENT

Director, National Institute of Dental Research

Public Health Service

COMMITTEE ON APPROPRIATIONS
1961 ESTIMATE
for
Dental Health Activities

Mr. Chairman and Members of the Committee:

The following statements will review for this Committee progress
made by the National Institute of Dental Research, the Division of
Dental Public Health and the Division of Dental Resources in their
respective missions to achieve and apply workable methods for the
detection, prevention and treatment of oral diseases.

Many aspects of the commonly occurring disorders of the mouth
and adjacent structures continue to challenge an increasing variety
of dental investigators today. Moreover, the dental profession is
cognizant of the increasing responsibility it shares with the other
health professions for the treatment and prevention of certain systemic
disorders including among others congenital oral anomalies and oral
manifestations of diseases such as blood dyscrasia, nutritional
deficiencies, etc.

Nineteen sixty has been a year punctuated with achievements of
important long-term and short-term goals. For example, basic and
clinical research efforts have expanded not only in our Bethesda
laboratories but expecially in nonfederal institutions receiving grant
support throughout the country. Further, the application of what is

- 2 -

now known about treatment and control of oral disease has been extended

and greater emphasis is being placed on advancing public and profes-
sional awareness of such research findings.

Undoubtedly, the most significant development for the control of
tooth decay in the history of preventive dentistry was the discovery
of the benefits related to fluoridation. However, even in the face of
this significant advance efforts continue toward the development of
additional preventive measures. For example, recent experimental data
from our laboratories provide evidence that a marked reduction in dental
caries may be effected by dietary supplements of phosphate minerals.
Clinical studies now under way are designed to extend our knowledge
of the effects of these compounds on caries reduction.

In addition, studies with germfree animals have provided
important new information on the bacterial causes of dental caries,
as well as on the relationship of the oral flora and various nutri-
tional factors to tartar formation and the onset and progression of
periodontal disease. These and related clinical studies have already
demonstrated that both tartar-like material and periodontal disease can
occur in the absence of oral bacteria. Data from these experiments
with the germfree and the gnotobiotic animals, continue to provide a
firm foundation for totally new concepts in dental research.

In the area of experimental caries research observations have
been made this year which indicate that dental caries is an infectious
and transmissible disease in hamsters and rats. From these findings it
is evident that the usual source of the caries producing microbial
flora in young animals is from the alimentary tract of the mother; and

- 3 -
that animals lacking this flora may acquire it by cross -infection
contact with caries-active animals D Work now in progress suggests that
there may be limitations either in the extent to which the flora of
one species can be transmitted to another, or in the degree to which it
will be pathogenic if transmitted. This observation may explain in
part why previous attempts to induce caries in laboratory animals by
inoculation of human strains of bacteria have failed,,

The Dental Health Activities of the Public Health Service embrace
not only the conduct and support of research and training, but also
the provision of consultative technical assistance to state and local
dental programs, and the development of dental resources „ From this
last area, that of dental resources, we learn, for example, that the
number of practicing dentists has been losing ground to population
growth in this country for more than a quarter of a century. If current
trends continue, the present ratio of 46 per 100,000 population will
decline to 43 per 100,000 by 1975.

We must of course, depend on our dental schools to provide us
not only with more practitioners but with persons trained in teaching
and research methods. A conservative estimate is that 650 teachers/
researchers per year will be needed in the next decade. During 1960,
progress was seen both in the awarding of additional fellowships,
primarily in the basic sciences, and in the establishment of seven new
research training centers and supplemental support to expand current
training programs. By the end of 1960, after only 3 years of program
operation, 25 graduate training centers will be supporting approximately

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130 trainees in both the basic and clinical sciences,, Results from
this modest but successful program are seen today in the some 40 to
50 trainees who will complete their training in I960,

In the area of Research Project Grants, increased funds in
1960 have provided for active program expansion in the broad areas
of periodontal disease, oral congenital anomalies (cleft lip/palate)
and dental caries. At the same time, emphasis was directed toward other
important facets of dental research, such as oral-systemic interrelation-
ships of chronic disease, electromyographic studies of the jaw, dental
radiation investigations, aging studies, and on dental public health
research.

Highlight activities of the Division of Dental Resources in 1960
included assistance to states and regions in planning for needed dental
school facilities. In addition, an experimental program was launched
to determine the optimum course requirements for the training of the
dental chair-side assistant. This study is a logical extension of
current programs designed to train dental students in the use of such
assistants. Also under study in I960 were a number of pre- arid poetdental
payment plans serving specific population groups.

In the Division of Dental Public Health, emphasis is currently
being placed on consultative and technical assistance to communities
of 2,500 population or less, as only 67o of these are now benefiting from
controlled water fluoridation. Increased funds in 1960 made it possible
to proceed with implementation of a study to develop a practical system
for fluoridation of individual home water supplies to meet the needs of
the approximately 1/3 of our population which does not have access to
communal water supplies.

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In conclusion, Mr. Chairman, the appropriation request for
the Dental Health Activities in 1961 is a total of $11,204,000 as
compared with the appropriation of $10,019,000 for 1960. This
allowance for 1961 will provide for the continuation of 1960 program
levels in all activities and will permit some increase in grants for
research projects and minor increases in the direct research activities
which include $400,000 for equipment for the new dental building and
$34,000 for clinical investigations. This request for 1961 is
distributed among program activities as follows:
G rants :

Research projects --------------$ 5,246,000

Research fellowships ------------ 650 9 000

Training 1,009,000

Direct Operations :

Research ----- 2,021,000

Review and approval of grants -------- 217,000

Professional and technical assistance - - - - 1,192,000

Coordination & development of dental resources 774,000
Administration --------------- 95,000

TOTAL 11,204,000

OPENING STATEMENT
by
Director, National Institute of Dental Research
Public Health Service

COMMITTEE ON APPROPRIATIONS
1961 ESTIMATE
for
"Dental Health Activities"

Mr. Chairman and Members of the Committee:

The following statements will review for this Committee,
progress made by the National Institute of Dental Research, the
Division of Dental Public Health and the Division of Dental Resources
in their respective missions to achieve and apply workable methods for
the detection, prevention and treatment of oral diseases.

Many aspects of the commonly occurring disorders of the mouth
and adjacent structures continue to challenge an increasing variety
of dental investigators today. Nevertheless, we consider this past
year to have been a very fruitful one--a year that has witnessed
achievements of certain long-term and short-term goals. Basic and
clinical research efforts have expanded not only in our Bethesda
laboratories but especially in nonfederal institutions receiving
grant support throughout the country. Further, the application of
what is now known about treatment and control of oral diseases has
been extended in a number of areas and greater emphasis is being
placed on advancing public awareness of these research findings.
Additional programs designed to increase the number and quality of
trained scientific investigators, teachers, and skilled clinicians
oriented in the dental sciences were also initiated during the past
year.

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Some of the accomplishments and developments of the Dental
Health Activities' total program which have occurred during the
current year are set forth in the ensuing pages of this statement.
The budget proposal before you requests an appropriation of
$11,204,000 for support of these activities in 1961.
Oral Disease Today

Nine out of every ten persons in these United States are
affected by one or more forms of dental disease — tooth decay, perio-
dontal disease, fluorosis, malocclusion, cleft lip and palate and
oral cancer. In spite of the 1.7 billion dollars expended each year
for dental services, the nation's accumulated dental needs are several
times greater than the needs currently being met. Tooth decay continues
to dominate the field of dental disease; however, statistics now being
gathered show that periodontal disease is currently a problem of
major national importance and might soon pass caries as the leading
cause of tooth loss in this country. Available clinical data tell
us, for example, that 22.5 million persons now require treatment or
extractions for periodontal disease and an additional 40 million
persons need preventive treatment. To meet these treatment needs
alone would involve close to three-quarters of a billion dollars in
dental bills.

Of further concern today is the knowledge that more than 4
per cent of all cancer occurs in the oral cavity, and it is five times
more prevalent in the oral cavity of males than females. Cancer of
the head and neck is responsible annually for the death of approxi-
mately 20,000 persons in this country.

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Consideration of these overall statistics associated with
oral disease serve to demonstrate the difficult problems that still
await the attention of dental scientists. However, new findings
introduced through laboratory and clinical research during the past
year have added significantly to the existing body of knowledge in
terms of diagnosis, treatment, and general understanding of disease
mechanisms.

The Dental Health Activities of the Public Health Service
function today in the conduct and support of research and training,
the provision of consultative technical assistance to state and
local dental programs, and the development of dental resources. In
this last area, that of dental resources, we know that the number of
practicing dentists has been losing ground to population growth in this
country for more than a quarter of a century. During this period, the
number of dental practitioners actually serving the civilian population
has fallen from 58 to 46 per 100,000 persons. If current trends
continue, this ratio will decline to 43 per 100,000 persons by 1975.

We must, of course, depend on our dental schools to provide
us not only with more practitioners but with persons trained in
teaching and research methods. At the present time, dental schools
almost uniformly report pressing problems in faculty recruitment and
retention. To a disturbing degree faculty positions are being filled
by practitioners who devote only a few hours a week to part-time
teaching. Further, we know that strengthening the dental faculties by
increasing the permanent full-time positions, with adequate opportun-
ities for research and experimentation must receive priority support

- 4 -

beyond our present level. It is against this background of
recognized dental health needs that we wish to report to the
Committee on current developments and aspirations of the several
programs of the Dental Health Activities of the Public Health Service.

DIRECT RESEARCH

The intramural research program of the National Institute of
Dental Research is devoted to the development of effective methods
for the prevention and control of dental diseases and related local
and systemic conditions. The Institute's program is concerned with
conducting and fostering investigations in fundamental oral biology
as well as in matters directly relating to the causes, prevention,
diagnosis and treatment of disease conditions of the oral cavity and
its associated structures. The most prevalent of these conditions
are dental caries, periodontal disease, bacterial and viral infections,
and congenital anomalies. Because of the multiple and nonspecific
etiology of many of these conditions, it is often necessary to isolate
each of the various causal factors and study their effects alone, as
well as in combination with each other. Such program objectives are
achieved by the cooperative work of diversified scientific disciplines,
including biochemistry, microbiology, genetics, oral pathology,
histology, embryology and epidemiology.

Undoubtedly, the most significant development in the history
of preventive dentistry is the discovery in recent years of the oral
health benefits related to fluoridation. Although dental caries is
still a major health problem, each passing year sees progressive
benefits to communities having fluoridated drinking water, However,

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even in the face of this significant advance, efforts continue to
be directed tov/ard the development of additional preventive measures.
Recent and current research now provides substantial experimental
evidence that an appreciable reduction in dental caries can be
effected by dietary supplements of phosphate minerals. In addition,
studies with germfree animals are providing important new information
on the bacterial causes of dental caries, as well as on the relation-
ship of the oral flora and various nutritional factors to calculus
formation and the onset and progression of periodontal disease.

Periodontal disease (pyorrhea), the main cause of loss of teeth
in adults, continues to be a major research responsibility. Signifi-
cant progress is being made in our understanding of this condition
through the recent expansion of epidemiologic and biometric studies
of selected population groups in this country and abroad. Such an
approach has contributed information not only to the question of
prevalence and severity, but also to the further development and
testing of methods for assessment of this disease. In addition,
basic studies are under way in the fields of oral bacteriology, using
germfree animals to assess the cause and effect of tartar formation;
and, in biochemistry to determine the nutritional and enzymatic
relationships to periodontal disease.

Fundamental research on cleft palate and other congenital
anomalies involving growth and development of the facial region has
long been a neglected area in dental as well as in medical research.
These structural growth deformities are primarily an oral problem
and there is a large diversity of professional interest involving

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the fields of maxillofacial surgery, orthodontia, prosthodontia,
speech pathology and therapy, otolaryngology, psychology, and genetics.
Gnotobiotic Program

During the current year, gerrafree animals have been used to
provide a controlled situation for testing the pathogenic effects of
oral microorganisms singly and in defined combinations, and for
evaluating the influence of constitutional and dietary factors on
controlled disease processes. Unlike the great majority of infectious
diseases, the lesions of tooth decay and periodontal disease harbor
a variety of microorganims that are normally present in every mouth.
Heretofore, it has not been possible to demonstrate the causal
significance of any one organism or group of organisms. However,
the Dental Institute's program in the germfree area has resulted in
certain significant observations of sufficient importance to require
reexamination and possible revision of present basic concepts ?e-
garding the etiology of dental caries and periodontal disease. For
example, in addition to our recently acquired knowledge that dental
decay does not occur in germfree animals, even when they are main-
tained on an otherwise caries producing diet, we are now able to induce
extensive tooth decay in "germfree" rats when they are infected with
a single strain of bacteria (a streptococcus) obtained from caries
active animals. Since it is unlikely that a single organism is
responsible for tooth decay, studies will be continued at the present
level in order to discover the nature and contribution of other oral
microorganisms to the caries process.

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Another significant development in the Institute's gnotobiotic
program is related to highly suggestive evidence that calculus (tartar)
formation may occur in the absence of bacteria. Since such deposits
are an important contributing factor to the development of periodontal
disease, and have previously been thought to be due to microbial
activity, this research activity will be vigorously pursued in the
coming year.
Nutritional Program

A new approach to the control of dental caries is currently
being explored by Dental Institute scientists in a cooperative study
with other federal agencies and private institutions. This clinical
investigation is based on the recently acquired evidence that dental
decay in rats is dramatically reduced by adding a mineral phosphate
to the diet. In large measure, this pronounced anticaries effect was
achieved by incorporating dibasic calcium phosphate in the bread
flour used to prepare the experimental diets. The fact that flour
for human consumption may be "phosphated" has already been demonstrated
by the widespread use throughout the Ration of self- rising bread and
certain cake mixes which contain a similar compound.

The presently operating clinical study is located in a number
of selected children's boarding schools in South Dakota. With equal
division into control groups and those which are receiving the mineral
additive in the dietary, it is expected that annual examinations for
the next several years will provide an indication of possible benefits
to caries control.

- 8 -

Interest in this dietary experiment extends beyond the area
of dental health. Inasmuch as the calcium as well as the phosphate
content, of the children's diet is being increased, routine obser-
vations on possible benefits to general health, and particularly bone
development and body growth, comprise an essential part of the study.
Experimental Caries Research

During the current year, observations have been made which
indicate that dental caries is an infectious and transmissible disease
in hamsters and rats. These findings already have had widespread
significance in the field of experimental caries research because
they explain a number of phenomena involving resistance and suscepti-
bility to caries that were formerly attributed to genetic factors and
to systemic developmental effects presumably induced by diet and
nutrition.

On the basis of now completed studies, it is evident that the
usual source of the caries producing microbial flora in young animals
is from the alimentary tract of the mother; and that animals lacking
this flora may acquire it by cross infection contact with caries active
animals. However, while the cariogenic flora can be transmitted
between members of the same strains, it is not ubiquitous in the
general laboratory environment and may, in fact, require considerable
time to become established at pathogenic levels. Work now in progress
suggests that there may be limitations either in the extent to which
the flora of one species can be transmitted to another, or in the de-
gree to which it will be pathogenic if transmitted. This observation

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may explain, in part, why previous attempts to induce caries in
laboratory animals by the inoculation of non- indigenous (human)
strains of bacteria have failed.

Thus a significant contribution has been made in the current
year which provides a firm basis for more definitive studies of factors
influencing dental caries.
Genetics Program

Studies of hereditary defects in dental tissues, begun several
years ago among isolated and inbred population groups in this country
and Japan have been directed toward (1) a study of mechanisms of in-
heritance of known hereditary diseases; (2) an evaluation of the role
of heredity in other diseases not generally considered to be genetic;
and (3) an elucidation of the underlying processes involved in hereditary
disorders.

It is hoped that recent advancements in our knowledge of the
structure of chromosomes and genes, and the separation of spermatocytes
containing different chromosomes, will open the way for newer methods
of controlling or preventing hereditary disease. Additional objectives
relate to the identification of those social patterns in our communities
which influence the prevalence and distribution of intrinsic disease.
Such knowledge would aid significantly in case finding and early
diagnosis of genetic diseases during their incipient stages when they
might be more susceptible to treatment.
Epidemiology Program

During the current year emphasis has been placed on the develop-
ment and testing of field methods for the measurement of periodontal
and other oral diseases in population groups. One important phase of

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this program, conducted in collaboration with the Interdepartmental
Committee on Nutrition for National Defense, has been to compare the
prevalence of oral disease in individuals living under relatively
civilized conditions with that of individuals in primitive villages
of Alaska, Peru, Ecuador, and Ethiopia. Findings, to date, show a
relative rarity of dental caries and periodontal disease in many of
these primitive groups.

Other projects receiving particular attention during 1960 have
been the epidemiology of dental caries with particular attention to
the fluoride-caries relationship; and an investigation of the influence
of familial factors and of geographic location of periodontal disease
and dental caries among Seventh Day Adventist families. The former
program is providing evidence that caries inhibition is a simple
function of the time available to a tooth for accumulation of fluorides
prior to eruption, With reference to the latter study, a consistently
low caries rate found in Adventist children may possibly be related
to the dietary recommendation of the "health reform" suggested by
the Adventist Church.

RESEARCH GRANTS

Increased funds in 1960 have provided for active program
expansion in the following broad areas: (1) periodontal disease, (2)
oral congenital anomalies (cleft lip/palate), and (3) dental caries.
At the same time, emphasis was directed toward other important facets
of dental research, such as oral-systemic interrelationships of chronic
disease, electromyographic studies of the jaw, dental radiation in-
vestigations, aging studies, and on dental public health research.

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During this year, particular interest was focused on studies
involving periodontal disease. Its etiology is virtually unknown;
damage to the periodontal tissues is irreparable; and, treatment for
this disease is empirical. Research investigations are now being con-
ducted on dental calculus and its etiologic role, malocclusion factors,
and contributing nutritional systemic relationships, as well as in
basic studies involving the biochemistry, physiology, and morphology
of the periodontal tissues.

Research in cleft lip palate requires multidisciplinary co-
operative effort on the part of both clinical and basic science
researchers. Costly hospital and clinical facilities are required, to-
gether with highly skilled and well trained personnel in several pro-
fessions and specialities, New clinical projects designed for a co-
ordinated attack toward solving some of the major problems in this
field were initiated this year in university-affiliated hospitals and
cleft palate clinics.

While significant advances have been made in the control of
dental caries, no single factor has thus far emerged as determinant
in the etiology of this disease. During 1960 added support was given
for bacteriological, salivary, and biochemical studies aimed toward
filling gaps in the void of knowledge concerning this important oral
disease.

Other support during the year was programed for electromyographic
investigations of masticatory structures because there is a strong
indication that such information will go far toward solving some of
the serious clinical problems of malocclusion, temporomandibular joint

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dysfunction, and denture prosthesis. Increased support in FY 1960
for radiation studies related to dental practice was another important
aspect of the grants programs. Particular attention is now being
directed toward aging studies, oral systemic chronic disease relation-
ships, and broad studies of dental public health problems.

FELLOWSHIPS

The primary efforts of the research fellowship program are
directed toward graduate training in the basic sciences with special
emphasis on increasing the number of individuals trained in the basic
sciences related to the study of periodontal disease, cleft palate,
dental caries, and other oral diseases. In dental schools today there
is a shortage of teachers trained in research techniques and as the
schools broaden their curriculum and increase and modernize their
research facilities, this shortage becomes more acute. Continued and
increased use of the fellowship program is therefore necessary to
staff the basic science departments and increase the research potential
of the 47 dental schools throughout the country. The Institute, recog-
nizing the need for competently trained personnel, has therefore,
sought to support sound research training, to encourage training in
certain critical fields, and to anticipate the demand for support from
the growing number of graduate students.

The research fellowship program as presently constituted is
divided into four types of awards: (1) dental student part-time
fellowships; (2) predoctoral fellowships; (3) postdoctoral fellowships,
and (4) special fellowships.

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Dental Student Part-Time

The dental student part-time fellowship program is aimed at
encouraging undergraduate dental students to give consideration to
a career in academic dentistry and research. Analysis of the program,
instituted in 1955, shows that a substantial number of students trained
during the first five years have continued in academic dentistry and
research. Currently, support at the level of eight units per school
is available to all 47 dental schools. In 1961 the program will be
extended to the schools of public health with at least two units to
a school. By this means, dental students will be afforded the op-
portunity of research experience during the summer period.
Predoctoral

Predoctoral research fellowships are awarded to qualified
persons with a bachelor's degree who wish to undertake research in
the fields of basic sciences related to dentistry. Such support also
fosters the research- trained teacher program.
Postdoctoral

The objective of the postdoctoral program is to increase the
number of dentally-trained personnel competent to conduct basic
research as related problems of oral diseases. This program is a
natural continuation of the dental student part-time program; experi-
ence demonstrates that more and more of the part-time dental student
fellows are applying for postdoctoral support following graduation.
The increased funds made available for this program in 1960 are pro-
viding for ten additional postdoctoral fellowships.

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Special

Parallel with the increased number of dental researchers, the
need for special types of training over and above the postdoctoral
level has also increased, This type of award is made to the more
advanced scholar and is especially beneficial to the investigator
trained in a particular field who wishes to acquire a multidisciplinary
approach often lacking in today's dental health research. Two
additional special fellowships will be awarded this year.

TRAINING

The primary objective of the graduate training program is to
increase the number of competent clinical researchers and/or teachers
in dental schools and other dental research institutions throughout
the U. S., thereby offsetting somewhat the current shortage of teacher-
researchers presently available to these institutions. Increased
physical facilities are now being built by many dental research
institutions. Several new dental schools are projected during the
next decade and each will require substantial numbers of additional
personnel for research and teaching.

There are three general kinds of training grants administered
by the Dental Institute: (1) relatively larger grants for broad
research training centers in a limited number of well-established
dental research institutions, (2) grants to some schools to establish
programs in only a single area of training because of certain special
facilities in terms of research and personnel available, (3) smaller
training grants to schools with less research and training potential
to enable younger faculty members to go elsewhere for special training.

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During 1960 progress in the area of training was seen in the
establishment of seven additional research training centers and in
supplemental support to expand current training programs. By the end
of 1960, after only 3 years of program operation, twenty-five graduate
training centers and other training institutions will be supporting
approximately 130 trainees in both the basic and clinical sciences.
Beneficial results from this modest but successful program are now
seen in the some forty to fifty trainees who will complete their
training in 1960. The great majority of these individuals will accept
academic appointments when their training is completed.

DENTAL PUBLIC HEALTH

The Division of Dental Public Health, through its program of
technical assistance, strives to prevent and control dental diseases
through a series of integrated steps which may be viewed as a continuum.

This continuum involves recognition of basic research discoveries
which may have application in public health programs, further develop-
ment or modification of such discoveries through applied technical or
administrative studies, and the provision of consultation and technical
assistance to States and communities in achieving rapid and extensive
application of new and effective means of coping with the dental disease
problem. Such consultaion, the major, continuing responsibility of
this program, is provided by well-qualified staff in eight regional
offices,

Following are the major areas of activity identified with the
technical assistance program.

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Fluoridation

The extension of the protection which fluoridation provides
for the prevention of tooth decay continues to be a major goal of
this activity. Slow but steady progress is evident in the complementary
efforts of official and voluntary agencies and organizations to secure
fluoridation of public water supplies. Currently, it is estimated that
about one-third of the 100 million persons on public water supplies
are receiving fluoridated water. The total national expenditure for
community water fluoridation programs is approximately one-half
million dollars. The tooth decay that is prevented by these programs
would cost 50 million dollars to repair. This reduction in need for
fillings makes additional chair time available for the treatment of
other dental ills.

The adoption of fluoridation throughout the Nation, however,
remains a great challenge. For example, while a majority of the cities
with populations of one-half million or more use fluoridated water,
only 6 percent of the communities with populations under 2,500 are
doing so.- Special emphasis is to be given in providing consultative
technical assistance to these smaller communities.

Although more than 35 million people in over 1,£50 communities
served by public water supplies are now receiving the benefits of
fluoridated water for prevention of decayed teeth, more than one-third
of the population of the United States may never be able to enjoy these
benefits because they consume water obtained from individual home water
supplies. To meet this special need, a study has been implemented
in 1960 to obtain data on the degree of acceptance and cost of providing

- 17 -

fluoridation to individual homes, and on attendant administrative and
technical problems. Continuation of this study in 1961 will provide
the necessary information upon which to evaluate the practicability
of extending a home fluoridation system to families throughout the Nation.
Health Practices

It is increasingly evident that infectious diseases and chronic
illnesses, including dental diseases, can neither be totally arrested
nor prevented without the voluntary participation of individuals in
necessary health practices.

Increased attention is being given this year to the exploration
of reasons why individuals accept or reject dental services and pre-
ventive health practices, A study started in 1959 in New York State
by the Division is in the late analysis stage. Another study has
been completed regarding the acceptance of dental care by nursing
home populations in Kansas City, Missouri.

During 1960, limited studies of community response to positive
health measures and practices have been initiated. It is hoped that
a beginning can be made in setting up experimental situations to identify
specific, important educational factors which are instrumental in
changing people's dental health attitudes and behavior. These controlled
situations will expose high school students to educational materials
based on behavioral hypotheses which have emerged from the New York
and Missouri studies. Analysis will be made of changes in the students'
attitudes toward dental practices and actual changes in dental practices
as a result of exposure to the different dental health educational
materials.

- 18 -

Such studies potentially have very practical application.
Information derived from them can help the administrator to develop
programs which will motivate the greatest number of people to act in
a way most conducive to preserving and improving their own health.
Dental Auxiliaries

The enormity of the dental health problem in the United States is
further aggravated by the severe shortage of dentists to provide
treatment for dental diseases. For the past third of a century, the
supply of dentists in proportion to the population has been steadily
shrinking. To increase the productivity of the dentist now in practice
through expanded use of auxiliary dental personnel, a community-wide
study is being undertaken to develop effective methods for the in-service
training of private practicing dentists in the utilization of the
chair-side dental assistant. Under the direction of a State health
department, private dental practitioners will be trained in new and
advanced procedures for utilizing assistants. Complementary training
of assistants will be undertaken in conjunction with the instruction
of dentists. This study is to be continued in 1961 far the purpose of
appraising and improving the methods employed for training the private
practicing dentist and assistant as a basis for more widely implementing
such post-professional education programs throughout the Nation.
The Chronically 111

Studies were initiated during 1957 to develop specific information
concerning the nature and extent of the dental service needs of the
chronically ill and aged; to identify and solve technical and adminis-
trative problems associated with making dental services available to

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such persons; and to develop specialized equipment, clinical
techniques and methods necessary for providing dental care services
to these persons. These studies are being evaluated and preliminary
findings have been prepared. During 1960 all patients participating
in these studies are being placed on maintenance dental care. This
will permit the staff to concentrate on organizing community re-
sources to carry on the projects after completion of the study, and
to evaluate the effectiveness of methods used to obtain community
participation and interest in such projects. The applied research
phase of this project will be completed by the close of 1961 at
which time more will be known about applying and implementing this
new knowledge in other communities throughout the Nation.
Career Development

During 1960 continued emphasis is being given to career
development for Public Health Service dental officers by providing
formal training in schools of public health and work experience in
regional offices of the Service and in State health departments.
Such training will help to insure a continuing supply of trained
personnel for dental public health activities of the Service.

DENTAL RESOURCES
Although the American people today enjoy the highest standard
of dental health in the world, it is a standard under which 60 percent
of our people get no care at all within any one year and still others
receive only the emergency services necessary for the relief of pain.
Now, with the almost certain prospect that the better-educated citizens
of tomorrow will seek a higher standard of dental health, there is the

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- 20 -

serious possibility that the dental profession will be unable to
supply services to all who seek them.

Increases in dental supply have been lagging behind population
growth for more than a generation. As a result, the number of dentists
serving the civilian population has fallen from a previous high of
58 per 100,000 persons to 46 today. Should all expansion in school
capacity now planned be actuallyrealized, the number of additional
graduates produced would still fail to halt the downtrend. Probably
at best, today's schools can expand graduating classes to produce
another 450 dentists per year. But to maintain the supply of dentists
even at today's inadequate level--a level reflecting almost 30 years
of steady decline--would require at least 2,700 additional graduates
each year.

One of the major functions of the Division is to assist States
and regions in planning for needed school expansion. Completion of
manpower surveys of the Midwestern and Mid-Atlantic states this year
brought the total number of regional analyses of long-range manpower
trends to six. The series now enjoys wide use by regional and state
groups as a basis for planning and as models for similar studies
of smaller areas. During the year, both the Western Interstate
Commission for Higher Education and the New England Board of Higher
Education took further action to implement the recommendations included
in the Division's earlier studies of their region's problems. In
New England a resolution reaffirming support of legislation permitting
construction of new dental schools in Connecticut and Massachusetts

::u

- 21 -

was approved by the Board. The Board further recommended the
immediate establishment of Schools of Dental Hygiene in Maine and
Rhode Island. In the West the Interstate Commission recommended
to the Western governors the immediate expansion of all existing
dental schools and the establishment of five new schools. More than
a dozen states were developing plans for expansion or construction
of dental and dental hygiene schools.

These and similar activities designed to increase the number
of dentists in practice are basic to all future dental health programs.
Alone, however, they are not enough. A growth in the number of
practicing dentists must be augmented by a major increase in dental
productivity through greater efficiency in the use of the dentist's
time. Such an increase depends not only on technological advances
but also, and probably to an even greater extent, upon a more wide-
spread and efficient utilization of the skills of auxiliary personnel.
The Division's activities in this area were breatly accelerated. Its
pioneer project to teach dental students how to work with dental
assistants was doubled during the year. A January 1959 conference
with dental school deans reviewed the initial three years of the
project and discussed directions the project could profitably take
in the future. In a new study, the Division began collecting data
for an evaluation of the impact that various types of dental assistant
programs now operated by these cooperating schools have upon attitudes
and practice techniques of dental students, both during college and
after they enter practice.

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- 22 -

To provide a larger supply of better qualified dental assistants,
the Division launched a new experimental program to determine the
type and length of schooling required for their training. A cooperating
junior college is offering two curriculums, one completed in a single
year, the other completed in two, and on the basis of this dual ex-
perience will make recommendations for a permanent, standardized
training course. At the same time, a city school system will offer
assistant training at the post-high school level in its public schools.
To buttress this and similar experiments, another providing an on-the-
spot study of tasks actually performed by assistants in private dental
offices was initiated.

As a corollary to activities aimed at increasing the availability
of dental services, the Division studies all aspects of dental demand.
One of the best indications of the increasing demand for dental care
is the recent growth of pre- and postpayment plans. This growth
heightens the need for dependable data on utilization patterns and on
those factors serving as barrier or stimulus to the purchase of service.
Intensified activity in studies of various types of dental payment
plans has resulted in the publication of a variety of monographs and
articles analyzing the salient features of the various plans. For
example, one study was designed to analyze the attitudes dentists hold
on the effects of a budget payment plan upon dental practice and
patient's welfare. These findings were also related to actual utilization
of the program by the dentists involved. Another study was begun
this year concerning the participation and attitudes of members of
Group Health Association Inc., with respect to that program's dental
plan.

- 23 -

In conclusion, Mr, Chairman, the appropriation request for
the Dental Health Activities in 1961 is a total of $11,204,000 as
compared with the appropriation of $10,019,000 for 1960. This al-
lowance for 1961 will provide for the continuation rf 1960 program
levels in all activities and will permit some increase in grants
for research projects and minor increases in the direct research
activities which include $400,000 for equipment for the new dental
building and $34,000 for clinical investigations. This request for
1961 is distributed among program activities as follows;
Grants ;

Research projects ---------------$ 5,246,000

Research fellowships ------------- 650,000

Training 1,009,000

Direct Operations ;

Research _-- 2,021,000

Review and approval of grants --------- 217,000

Professional and technical assistance ----- 1,192,000

Coordination & development of dental resources 774,000
Administration ---------------- 95,000

TOTAL 11,204,000

SUMMARY OF OPENING STATEMENT

Director, National Institute of Allergy and Infectious Diseases

Public Health Service

COMMITTEE ON APPROPRIATIONS

1961 ESTIMATE

for

'Allergy and Infectious Disease Activities"

Mr. Chairman and Members of the Committee:

The infectious disease activities of this Institute evolved from
the earliest Public Health Service research. Allergy- immunology studies
were assigned in 195&-

Emphasis is placed upon the need for trained microbiologists, a
central resource for all medical research.

Upper respiratory diseases (a $3 billion medical bill and a $2
billion annual loss to industry) represent an expanding field of study.
Important causes of respiratory diseases, such as the parainfluenza viruses
and viral agents in pneumonia, are being delineated. Vaccines are under
development. Basic work on a number of microbial agents is also under way.

The growth of allergy research, now emphasizing basic immunology and
airborne allergens, is reflected in a two-year increase from 150 to 250
grantee studies. Attempts are being made to standardize allergens employed
by various investigators.

Cystic fibrosis and staphylococcal infections are problems receiving
special attention. The Institute is supporting a national survey to deter-
mine the incidence and mortality of cystic fibrosis. Fungus diseases which
develop in the wake of antibiotic or steroid treatment are also a growing

- 2 -
concern. A drug effective against skin fungus infections has "been
developed.

The Rocky Mountain Laboratory, Hamilton, Montana, and the Middle
America Research Unit, Panama Canal Zone, investigate diseases of worldwide
occurrence prevalent in their respective regions: Q fever and mosquito-
borne encephalitides, for examples.

As spokesman before Congress for the Gorgas Memorial Laboratory,
Republic of Panama, the Institute Director requests the maximum funds
authorized by made available to Gorgas. This amount is $250,000 for
research and $250,000 for construction of additional facilities.

The 196l appropriation request for the National Institute of Allergy
and Infectious Diseases is a total of $3^,739,000. This compares with
$3^,05^,000 for i960. The allowance for 1961 vail enable the Institute to
maintain all activities at approximately the i960 program levels, and will
permit an increase of $1,208,000 in research projects and minor increases in
direct operations. This request for 1961 is distributed among program
activities as follows:

Grants :

Research projects $22,777,000

Research fellowships 1,066,000

Training 2,709,000

Direct • Operations :

Research 7,l|-89,000

Review and Approval 509/ 000

Administration .,..<, 189,000

Total 3^,739,000

OPENING STATEIffiNT

by
Director, National Institute of Allergy and Infectious Diseases

Public Health Service

COMMITTEE ON APPROPRIATIONS
1961 ESTIMATE
for
"Allergy and Infectious Disease Activities"

Mr. Chairman and Members of the Committee:

The infectious disease activities at the National Institutes of
Health have evolved from the earliest Public Health Service research.
Allergy-immunology studies were assigned in 195& as additional program
responsibilities, and the National Microbiological Institute became the
National Institute of Allergy and Infectious Diseases.

The importance of this area of research is not restricted to the
infectious diseases or allergic disorders. Scientists trained in micro-
biology serve as a central resource for all of medical research. Their
skills are vital to the pursuit of studies of cancer, neurologic diseases,
cardiovascular disorders, and other major health problems.

The noncategorical nature of microbiology and its importance as a
"feeder" discipline are strikingly reflected in the scientific awards
presented this year by the Lasker Foundation to honor outstanding contri-
butions to medical research. All four of these distinguished prizes went
to microbiologists- -men representing the fields of immunology, virology
and epidemiology. One of the winners is Dr. Jules Freund, widely-imo\m
immunologist, who is a staff member of this Institute. The significance
of the work of these scientists cannot be assessed merely in terms of

- 2 -

infectious disease processes; it extends into and enriches all areas of
medical biology.

Thus, microbiological skills are a basic pre-requisite to progress
in many areas of public health research; the need for trained microbiolo-
gests is of paramount importance.

Research Training

High-quality medical research is the product of skilled,
thoroughly trained, dedicated scientists. The demand for such people far
exceeds the supply. The Nation must, therefore, recruit and train ade-
quately motivated young investigators. This is a prime responsibility of
a program such as that of the National Institute of Allergy and
Infectious Diseases.

Both the fellowships program and the training grants program of
this Institute are helping to meet the need for specialized research
training in the broad realm of microbiology, particularly with respect to
allergy and immunology, infectious diseases, and tropical medicine and
parasitology.

A research fellowship permits a promising young scientist to secure
needed training at a particular institution and under a particular mentor
best fitted to his needs. He takes his own financial support with him.
In 1958; 31 fellowships in the amount of ^113,000 were supported by this
Institute. In i960 the number had increased to 223 with an allocation of
^1,066,000. Only the most highly qualified students have been supported

- 3 -

by research fellowships from the National Institute of Allergy and
Infectious Diseases.

The training grant program provides funds not only to support the
trainees but also to meet the institution's need for additional staff,
equipment, and other items. In the 2 years that this Institute has had
such a program, more than 80 research training units have been established
or strengthened in the Nation's schools. A number of these are new pro-
grams in allergy and immunology, an area where opportunities for research
training have long been woefully inadequate.

Acceptance of the Institute's training grant program by teaching
institutions across the country is reflected in the rapid growth from 27
grants amounting to §56k,91k in 1958 > the first year of operation, to an
estimated 86 grants totaling $3*621,000 in I960.

Upper Respiratory Disease

More than 100 "new" viruses of man have been isolated since 19^-8 •
They undoubtedly cause much of the upper respiratory disease responsible
for about two-thirds of all our acute illness. The death of 20 million
people throughout the world from the 1918 influenza epidemic underscores
the fact that the respiratory disease problem cannot be equated simply
with the "common cold" or other comparatively minor syndromes- -although
these add to the general misery and multi-billion-dollar cost.

Statistics indicating the impact on public health and economy of
the respiratory diseases bear repeating: One million person-years lost

- k -

from work, housekeeping, or school during a 6-month period including the
1957 Asian influenza outbreak . . . Approximately 28 k million acute
respiratory illnesses serious enough to require medical attention in the
United States during that epidemic year, ending in June, 195& 1 • • • An
estimated 75 > 000 deaths associated with influenza in the same period . . .
A $3 "billion medical hill and a $2 "billion estimated annual loss to
industry due to the common respiratory diseases.

Respiratory virus research has undergone a steady expansion in the
last several years as increased funds became available both under the
research grants program and the Institute's direct operations. Much of
the recent progress in this area relates in some degree to the higher
support levels which characterize infectious disease research today.

In the virtual absence of effective drugs against viruses among
hundreds of compounds tested, the objective is prophylaxis through new or
improved vaccines. A prototype of such biologies is the adenovirus
vaccine first developed by this Institute in 1955 an <i shown through our
studies and those of the Ualter Reed A^y Institute of Research to be
effective in reducing respiratory disease in recruits. This is now being
produced cOi.imercially and the military has prepared plans and specifica-
tions for routinely administering adenovirus vaccine.

A striking example of the importance of knowing which viruses we
are dealing with is provided by continuing epidemiological work on the
hemadsorption viruses, first isolated by scientists o± this Institute and

- 5 -

Children's Hospital, D. C, in January 19^8. These cell-parasites, now
called parainfluenza viruses, were round responsible for 20 percent of
the respiratory disease in large groups of children at three Washington,
D. C hospitals. In contrast, Asian influenza --and this was during its
epidemic year- -caused only 13 percent of the respiratory disease in the
group. Since the newly isolated viruses caused symptoms that closely
resembled those of Asian influenza, one could reasonably conclude that
some cases of Asian influenza attributed to vaccine failure actually were
caused by the newly recognized viruses. Work is under way on a vaccine
against the parainfluenza group and other "new" viruses which cause
respiratory disease. If an effective biologic can be developed, it might
be combined with influenza strains in a polyvalent vaccine.

The new parainfluenza virus has also been isolated (in studies by
this Institute and USDA's Agricultural Research Service) from cattle
afflicted with shipping fever, a costly respiratory illness. Although
our primary interest is public health, veterinary medical advance should
be a valuable by-product of this research.

The atypical or viral pneumonias represent another serious clinical
problem in the respiratory field. A recent large-scale study in Marine
recruits has revealed that the Eaton virus (first isolated by Dr. Monroe
Eaton of Harvard) may be an important cause of non-bacterial penumonias
in military recruits. In this epidemiological work, the Institute co-
operated with the Navy Bureau oi' Medicine and Surgery and the Naval

- 6 -
Medical Research Unit at Camp Lejeune Marine Base, and with the Walter
Reed ..rmy Institute or Research. The relatively new technique of lagging
antibodies with fluorescent dye, which has proved so useful in quickly
identifying "strep" infections, was employed in these investigations. The
study is particularly important because it indicates a considerable involve-
ment of the Eaton virus in a type of pneumonia not previously linked with
a causative agent. Atypical pneumonia is often a serious clinical disease;
a vaccine might be warranted. The work is being extended to include more
than 1,000 new recruits at the Marine base.

Respiratory-related virus studies, ranging from work employing the
tobacco mosaic virus variant -system to elucidate the chemistry of mutation
(University of California) to observations of gene transfer by the phage
viruses that parasitize bacteria (University of Colorado) are a part of
our over-all research grants program in virology, which totals $3 million.
Many investigations under this program are directly related to clinical
respiratory disease. For example, Institute grantees at Harvard, Boston,
and Tufts university medical centers reported last spring on findings in
Asian influenza-associated fatalities. Their studies re-emphasized that
pregnant women and people with chronic heart disease or chronic respira-
tory insufficiency are particularly susceptible to severe influenzal
disease and are prime candidates for immunization.

. J.lei-gy-Immunology

rvn extensive urban survey of major allergies, conducted by a group
of New York investigators and reported at the 1959 annual meeting of the

- 7 -

:<jnerican College of Allergists, revealed these disorders to be twice as
prevalent in the general population and four times as prevalent in children
as previous estimates for the Nation had indicated. No small amount of
this illness is disabling and sometimes fatal. Crippling lung insuffi-
ciency from chronic asthma, and anaphylactic shock after drug injection
are examples of serious allergic sequalae .

An Institute immunologist employing facilities of New York Univer-
sity has shown that susceptibility to the form of brain damage known as
allergic encephalitis can be passively transferred from a sensitized and
susceptible rat to a normal rat by injection of lymph node cells from the
former. This will provide a useful model for studies of this allergic
mechanism which has a counterpart in man, for example, in the occasional
paralysis following vaccination against rabies.

The National advisory allergy and Infectious Diseases Council in
1959 held a scientific conference on allergen standardization attended by
30 of the Nation's foremost research immunologists. Out of the conference
came coordinated assignments designed to standardize ragweed pollen
extracts as a model system. Scientific investigators must have allergenic
products meeting rigid norms of potency, purity and specificity.

The growth of the allergy research program, first established in
the Public Health Service ^!- years ago, is reflected in an increasing number
of research project grants. Approximately 150 studies totaling $2 million
were supported by the Institute in 1958- In i960 support will approach §k
million for about 2^0 allergy-immunology grants.

- 8 -

Grantees at the University of California have shown, for example,
that mice subjected to stress have an increased resistance to allergic
shock- -a finding pertinent to investigations of the effect of environment
on susceptibility. In another study at Bellevue Medical Center, New York,
researchers are using radioactive isotopes to "label" allergens so they
can follow what happens during an allergic reaction in the skin. Many
industrial allergies are manifested in skin conditions. Ragweed pollen,
the most prevalent plant allergen in the United States, is also being
tagged by isotopes deposited in the plant. The grantees, working with the
aid of the Brookhaven National Laboratories, are attempting to trace, with
Geiger counters, the routes and distances travelled by the radioactive
pollen .

C ystic Fibrosis

In compliance with last year's Congressional request for more
accurate figures to outline the dimensions of the health problem presented
by cystic fibrosis, the National Institute of Allergy and Infectious
Diseases made available a special grant to the Children's Bureau and the
National Office of Vital Statistics for this purpose. Recently, these
agencies completed the first phase of their hospital survey, revealing
that approximately 2,500 cystic fibrosis patients, 95 percent under 20
years of age, were discharged from or died in hospitals during 1957*
Fatalities in the group numbered 359> °r 1^- percent. The survey team
emphasized that these figures represent only a fraction of the total

- 9 -

number of children suffering from cystic fibrosis. The University of
Nebraska, for example, reported kO children under treatment for this disease;
only k in this group had teen hospitalized.

The statisticians and medical scientists on the project are now
engaged in outlining methods to enlarge the survey by conducting a national
epidemiologic study of the disease. One of the more serious obstacles they
face is the absence of a simple diagnostic test for determining the presence
of the disease in the child. Currently the two methods considered most
reliable are duodenal intubation and the sweat test. Both, however, present
certain disadvantages. Scientists of our Laboratory of Clinical Investiga-
tion have been working for some time to solve this problem by developing
the diagnostic possibilities inherent in a simple blood test and a large-
scale investigation of this method is currently under way.

As a direct reflection of Congressional interest in this relatively
new disease, our program has undergone a rapid expansion during the past 2
years. For fiscal year i960 a total of $350>000 was allocated "co continue
studies aimed primarily at solving the severe problems of the secondary
infections attending this disease. Much of our initial progress in mobiliz-
ing against cystic fibrosis stems from this increased level of support both
for this Institute's program and complementary studies in the National
Institute of Arthritis and Metabolic Diseases.

It may also be added that the studies now in progress on staphylococ-
cal infections have a special pertinence to cystic fibrosis. While the
underlying defect in this disease is genetic in nature, the most critical

- 10 -

problem is the control of pulmonary infections to which these children are
especially susceptible. In one cystic fibrosis study involving 3^0
fatalities, it was shown that more than 9° percent occurred directly as a
result of chronic lung disease whose most striking feature is its associa-
tion with the staphylococcus agent. Thus it is clear that cystic fibrosis
patients will be the direct beneficiaries of anjr progress which science is
able to make against these widespread and persistent infections.

Staphylococcal Infections

The development of antibiotic-resistant strains of staphylococcus,
together with their widespread dissemination through hospitals and communi-
ties, continues to represent a -public health problem of highest priority.
In terms of morbidity and mortality, impact on other diseases, increased
costs of medical care, and special hazards for all hospital patients, the
staphylococcal problem is so well documented as to need little elaboration.

IJhat should be emphasized is the fact that this is not a phenomenon
peculiar to this species of bacteria. Rather, it is a problem which cuts
across a broad biologic front.

Most pertinent to this view is a warning issued by one of our grant-
supported scientists who recently reviewed patient records spanning a 2k-
year period at Boston City Hospital. It was his conclusion that the
favorable impact of the antibacterial drugs in reducing the number of
deaths from the pneumococcal pneumonias aud streptococcal infections has
now been more than overshadowed by an increase in deaths from staphylococ-
cal disease and from infections by other bacteria once considered

- 11 -

relatively harmless.

Because of the findings of this and similar studies, the problems
relating to antibiotic resistance are now regarded as the most immediately
urgent confronting hospitals. Scientists of this Institute are now attach-
ing this problem in studies designed to uncover basic knowledge of bhe
precise mechanisms by which the staphylococcus is able to produce disease
and resist therapeutic assault. One of the more fundamental of these
continuing studies in our Laboratory of Bacterial Diseases was devised to
furnish exact data on the degree of virulence which may be induced by
specific quantities of the standard staphylococcus strains, with the view
to using this information as a baseline for immunization tests.

In another study of the coliform species of bacteria, our scientists
have withdrawn, from the inner portion of the cell, certain of the soluble-
constituents containing the enzymes responsible for energy formation and
use. When these energy-forming systems were taken from susceptible strains
of the coliform species, they were shown to be inhibited in the presence o±
an antibiotic. This was not true for resistant strains. Such an experi-
ment pinpoints the particular locus of resistance in certain bacteria and
hopefully may lead to a prototype definition of the resistance mechanism
in general.

Our accelerated grants program, increased by $1 million in 1959
over previous levels and continued at this rate during the current year,
is now beginning to yield initial results. Much of the information being
received is e. .tremely fundamental, due to the poorly explored nature of

- 12 -

the subject under study. An an example, the research undertaken by one of
our grantees at the University of Colorado Medical Center has described a
plausible means by which resistance may be transferred to sensitive bacteria.
In a series of complex experiments, he has found evidence that certain of
the phage viruses which are known to parasitize bacteria may pirate the
resistance mechanism from one strain of staphylococcus and transfer it to
members of a strain previously susceptible to antibiotics.

Fungus Diseases

The growing realization that any great advance in the treatment of
disease is likely to introduce new medical problems arising out of man's
efforts to adjust to changes in his social and physiological equilibrium
is nowhere more clearly illustrated than in the rising incidence of fungus
disease. A recent study analyzing some aspects of hospital experience with
microbial infections today as compared with a period immediately preceding
the introduction of antimicrobial drugs reveals that fungus infections,
previously of little consequence as a cause of fatality, have now risen to
fourth place just behind the staphylococci, viruses and gram negative
bacilli. In many cases, fungus infections are superimposed on other
diseases initially prompting hospitalization. In view of this, the
National Institute of allergy and Infectious Diseases has undertaken to
strengthen its program in order to define more clearly the role of fungi
in human disease.

Findings include the recent disclosure by our laboratory scientists
of an intimate association between the house bat and the agent of

histoplasmosis, a pulmonary disease which may closely parallel the early
manifestations of tuberculosis. In another study our scientists have shown
that contact with pigeon droppings may result in a severe form of fungal
meningitis. The pigeon itself is not infected, tut its droppings serve as
an excellent culture medium for the airborne spores of the fungus.

This Institute has long supplied leadership in epidemiological
studies of fungus disease. Such investigations are now being extended into
clinical medicine through joint studies of our laboratory scientists and
clinical investigators. Their varied research activities include a
special pursuit of the possibilities of immunization against these diseases
and complete clinical trials of various drugs developed as curative agents.

Until the introduction of a new drug, amphotericin B, a i'ew years
ago, most patients afflicted with the serious disseminated forms of fungus
infection were compelled to struggle through the natural course of the
disease without the aid of an effective chemotherapeutic agent. Clinical
trials undertaken by our scientists in 1957 helped establish the usefulness
of this drug against certain of the serious systemic forms of these infec-
tions. Our laboratory scientists are continuing their search for new
drugs for the deeper fungal infections .

Perhaps the most encouraging immediate development to emerge from
the expanded program of fungus studies supported by the National Institute
of JJLergy and Infectious Diseases in vari.ous private institutions is the
recent introduction of systemic treatment against the superficial x'ungus

- Ik -

( ringworm) infections. During the past year, our grantees at the University
of Miami School of Medicine announced that griseofulvin, administered
orally to patients with a wide variety of typical ringworm infections, pro-
duced highly favorable results. Infections of long duration, up to 60 years
in one dramatic case, proved as susceptible to treatment as those of only a
few weeks' duration. Griseofulvin, under the trade names, Fulvicin and
Grifulvin, has now been licensed for manufacture by Schering and McNeill
Laboratories.

Rocky Mountain Laboratory
Historically noted for the conquest of Rocky Mountain spotted fever,
this field laboratory in Hamilton, Montana is today a modern two -million -
dollar research center. The main emphasis is upon diseases important to
the Western region of the United States, but many of these are also of
world-wide importance. With the continuing expansion of the work of this
Laboratory on behalf of the western states and the Nation, animal experi-
mentation, particularly with regard to diseases that in nature are trans -
metted from animals to man, has increased materially. Q, fever, Colorado
tick fever, tularemia, and equine encephalitis are examples of infections
of this type. In i960 Congress provided f' 150,000 for construction of ade-
quate animal facilities. Work is now under way on these, with foundation
poured and superstructure erected. The productivity of the Rocky Mountain
Laboratory investigators is reflected in the scientific literature. Some
of these recent research reports --on the epidemiology of influenza in an

isolated community, the growing hazard of Q fever, overwintering Ox Western
equine encephalitis virus, dissei.iination of rabies, reservoirs of Colorado
tick fever virus in nature , epidemiology of shi ellosis, tularemia surveil-
lance ^ and other findings are summarized in the "research highlights''
accompanying this statement,

Middle America Research Unit

Studies of arthropod-home virus infections continue to represent
the major emphasis of the Middle America Research Unit, which was established
'd years a^o in the Canal Zone. The Unit's virus studies were broadened in
the past year to include surveillance of the live poliovirus vaccine
(Lederle) program conducted by the Ministry of Health of Costa Rica under
PAHO-WHO sponsorship. Other virus projects include encephalomyocardi.tis in
swine and human epidemic influenza.

The Mycology Section of MARU, staffed by the Walter Reed Army
Institute of Research, has been extending its worl: on histoplasmosis,
particularly with reference to the significance of this fungus infection to
military personnel stationed in an area of historic histoplasmosis
endemicity.

When MARU was co-sponsored in October 1957 > by the NIH and WRAIR with
the cooperation of Canal Zone officials, provision was made ±01- scientific
evaluation of the program after 2 years of operation. An ad hoc committee
selected for scientific and administrative competencies pertinent to the
mission conducted extensive studies, including site visits, and recommended

- 16 -

that MARU should continue as a permanent field station of the Public Health
Service . In its endorsement, the Committee commended the Director. of MARU,
Dr. Alexis Shelokov, for the excellent scientific organization he has
created in a short time; pointed out that considerable planning underlies
selection of the most worthwhile projects from an abundance of opportunities ,
recognized that occasional diagnostic service will be necessary but recom-
mended that service should be carried out only as directly related to
laboratory research; suggested a joint scientific advisory board for MARU
and Gorgas Memorial Laboratory, and envisioned more specific bi-lateral
agreements on MARU between the National Institutes of Health and the Pan
American Sanitary Bureau.

At Bethesda, the MARU- correlated unit on arthropod-borne viruses is
obtaining and stocking viruses and their diagnostic reagents for the
Laboratory of Tropical Virology. Over 150 arthropod-borne viruses are now
recognized. Most extensively studied by the Canal Zone group and its
Bethesda counterpart is the virus of Eastern equine encephalitis. This
disease is seen in the United States during sporadic epidemics notable for
a high fatality rate, such as the 1959 outbreaks in the New Jersey area.
Most of the arthropod viruses are carried by mosquitoes. Diseases caused
by these viruses still are x^oorly differentiated, but represent a consider-
able threat to public health in temperate as well as tropical areas
throughout the world. Yellow fever, one of the arthropod-borne group, is
under intensive study by the Gorgas Memorial Laboratory in the Republic of

- IT -

Panama, with MARU providing some technical assistance as requested.

The Gorgas Memorial Laboratory

The Gorgas Memorial Laboratory in the Republic of Panama is the
medical research unit of the Gorgas Mmeorial Institute of Tropical and
Preventive Medicine „ The Laboratory is an outpost for research on yellow
fever, malaria and other diseases endemic to Middle America and presenting
potential problems to adjacent areas and the United States. Jungle yellow
fever, for example, is advancing northward from South and Central America
at an average of 13 miles each month. The conditions which permit this
resurgence are under study. Gorgas scientists are exploring outbreaks of
encephalitis of types sporadically epidemic in the United States, as well
as the over-all area of arthrox^od-borne infections. They recently reported
the isolation of St. Louis encephalitis virus in Panama from human blood
and naturally infected mosquitoes- -the first recovery of the virus in
Middle America.

Gorgas investigators are also developing new information on Chagas'
disease and leishmaniasis. Sandflies of the man-biting Phlebotomus species
have now been artifically infected with leishmania in attempts to reproduce
this disease in laboratory animals which will then be used to screen for
better drugs .

On September 21, 1959; Public Law 36-296 authorized increasing the
annual appropriation from $150,000 to $250,000, and also authorized $250,000
for construction of additional facilities on land valued at over a

- 18 -

quarter-million dollars already in possession of Gorgas, a gift of the
Republic of Panama. A more extensive discussion of the research accomplish-
ments and mission of the Gorgas Memorial Laboratory , now in its 31st year,
is available in the Committee print on the Hearing relative to this increase,

Dr. Walter A. Bloedorn, President of the Gorgas Memorial Institute,
has submitted a copy of the operating budget for the Gorgas Memorial
Laboratory. They will be able to make good use of the total amount author-
ized. Primarily, they wish to increase the staff, rehabilitate the power
supply and plumbing systems, develop more space for small animals, and pro-
cure equipment to provide for the added staff.

As spokesman for the Institute before Congress, I am requesting that
the maximum funds authorized by Congress be made available to the Gorgas
Memorial Institute of Tropical and Preventive Medicine during 1961.

Support of Institute Programs

The 1961 appropriation request for the National Institute of Allergy

and Infectious Diseases is a total of $3^> 739; 000. This compares with

$3^ ; 05^, 000 for i960. The allowance for 1961 will enable the Institute to

maintain all activities at approximately the i960 program levels. This

request for 1961 is distributed among program activities as follows:

Grants :

Research projects ^£^,777>00°

Research fellowships 1,066,000

Training 2,709, 000

- 19

Direct o perations :

Research 7,1*89,000

Review and Approval 509,000

Administration 189, 000

Total 3^,739,000

SUMMARY OF OPENING STATEMENT

Jirector, National Institute of Arthritis and Metabolic Diseases

Public Health Service

COMMITTEE ON APPROPRIATIONS
1961 ESTIMATE
for
"Arthritis and Metabolic Disease Activities' 1

Mr. Chairman and Members of the Committee:

The 1961 budget request for Arthritis and Metabolic Disease Activi-
ties which is before you is for $4-7,54.1,000 as compared to the appropriation
of ^6,862,000 for I960.

This year, I960, marks the tenth anniversary of the National Institute
of Arthritis and Metabolic Diseases. It has been a ten year period of
remarkable growth, highlighted by advances in both the basic sciences
and in clinical medicine.

In the rheumatic disease field the Institute is supporting a con-
siderable amount of research on hypersensitivity as a possible cause of
rheumatoid arthritis, and this research effort is showing increasing promise.
In gout treatment, new and better drugs are now available and we have been
able to further clarify the basic nature of this disorder. Diabetes research
continues to feel the impact of the oral antidiabetic drugs and possible new
uses for them have been discovered. Accomplishments in basic research were
highlighted this year by the awarding of the Nobel Prize in medicine for
work done on the synthesis of nucleic acids. One of the recipients was
a former chief of one of our laboratories and the other was a grantee of
the Institute.

n :■■?• '',

In addition to strengthening the research and training programs
in all our areas of responsibility, we are vigorously extending our
efforts in newer fields of interest such as cystic fibrosis, gastro-
enterology and international nutrition studies.

The appropriation request for 1961 represents an increase of
?679,000 over the appropriation of M.6,862,000 for I960. This allowance
for 196l will provide for the continuation of I960 program levels in all
activities and will permit some increase in grants for research projects
and minor increases in direct research activities, principally in cystic
fibrosis, gastroenterology and nutritional research under germfree
conditions. This request for 1961 is distributed among program activities
as follows:

Grants:

Research projects • J> 2,153 000

Research fellowships 437 000

Training grants 6,291,000

Direct research and supporting services ■ -8,653 ,000

Total 47,541,000

OPENING STATEMENT

Director, National Institute of Arthritis and Metabolic Diseases

Public Health Service
COMMITTEE ON APPROPRIATIONS
1961 ESTIMATE
for
"National Institute of Arthritis and Metabolic Diseases' 1

Mr. Chairman and Members of the Committee:

This year, I960 marks the tenth anniversary of the National
Institute of Arthritis and Metabolic Diseases. It has been a ten-
year period of remarkable growth, highlighted by advances in both the
basic sciences and in clinical medicine. At this time, and before we
move into the ne:-:t decade , I should like to review with the Committee
some of the accomplishments of these first ten years, and describe to
you the excellent progress made during this first decade in three areas
of special interest, rheumatic diseases, diabetes and basic research -
metabolism. The second portion of this statement describes the new
developments of the current year, the new areas into which our scientists
are now extending their vigorous efforts, particular attention being
given to cystic fibrosis and gastroenterology.

The advances to be described have resulted from work done both in
our own laboratories in Bethesda and in the many non-governmental
institutions throughout the country receiving support from this Institute
in the form of research grants, training grants, traineeships and
fellowships.

RHEUMATIC DISEASES

Ten Years of Progress . Only slightly more than ten years ago,
just prior to the momentous discovery of cortisone 's effects and the
establishment of the Institute, the rheumatic disease field was one of
the most neglected areas in medicine. For hundreds of years there had
been little real progress either in the understanding or in the treatment
of these diseases, although they affected an estimated ten million people,
Most physicians shared the sentiment once expressed by the great
Dr. : Jilliam Osier — "'When an arthritic comes in the front door, I want
to go out the back door . '■

There was no specific form of therapy for these diseases and
relatively little was being done for sufferers from them. Of the entire
number of beds available in university hospitals throughout the country,
there were only 700 beds usually occupied by arthritics. At that time,
the total amount of money spent on research in the rheumatic diseases
was only $300,000, and this included both government and non-government
funds. Of this .^300,000, one- third was going to only three universities.
There was little clinical training of young physicians. Only eight
centers in the United States had well defined training programs in this
area.

Contrast this discouraging situation with the very hopeful one
that exists today. Under the auspices of this Institute alone over
^4,000,000 is being devoted this year to rheumatic disease research. A
tremendous increase has occurred in the amount of professional training

- 3 -
being carried on, primarily as a result of the Institute's traineeships
program and training grants program. The traineeships began in 1953
when the Institute supported 21 arthritis trainees in 14 different
institutions. Today, we are supporting 92 trainees in over j+0 institu-
tions. Also, due to the important activities of the Arthritis and
Rheumatism Foundation there are now more than 300 arthritis clinics
throughout the country.

New Forms of Treatment a As has been discussed with the Committee,
cortisone was first used in 1948 to treat patients with rheumatoid
arthritis. Since that time the pharmaceutical industry has developed a
whole spectrum of anti-inflammatory steroids. Continual modifications
of the original cortisone molecule has produced drugs that are not only
more potent than cortisone but also have less tendency to produce serious
side effects. During the past ten years many of these industry -developed
compounds have been tested in our Clinical Center at Bethesda and have
largely replaced cortisone.

It must be remembered, though } that these powerful new drugs may
make arthritics more comfortable 5 but they are not curing the underlying
disease. In many cases, the disease process continues even though the
pain has been relieved. It is for this reason that we believe basic
laboratory research is vital. We have yet to find the cause of the
rheumatic diseases and until we do it is quite unlikely that we will
be able to develop a specific curative agent.

4 -

For the past ten years the Institute has placed heavy emphasis
on basic research, both intramurally and extramurally > and we have
witnessed some very promising developments in the rheumatic disease field.
For example, we now know many of the biological details of these diseases,
not only how they affect the functioning of whole systems within the body
but also how they affect individual cells, causing subtle but very
important changes in metabolic processes. Solid advances have been made
along many fronts but I would like to mention one in particular,
albeit a very broad one, that relates to our search for the basic cause
of arthritis.

Arthritis and Hypersensitivity . Studies over the past ten years
have more and more clearly pointed to the possibility that rheumatoid
arthritis has an immunologic basis, and results from a state of hyper-
sensitivity. This implies that individuals develop the disease when
they become overly sensitive to substances within their body, possibly
to their own altered protein. Rheumatoid arthritis may therefore be a
disease of autosensitivity .

Fragmentary support for this theory has come from both clinical
and pathological studies. Especially interesting is the research on the
rheumatoid factor, a substance found in the serum of patients with
rheumatoid arthritis and one that is peculiar to these patients. The
rheumatoid factor has already been made use of as a diagnostic tool,
being the substance that is detected by various diagnostic tests
developed in part in our own laboratories and by our grantees.

•■ 1-.

- 5

It has now been shown that the rheumatoid factor, or more
correctly rheumatoid factors, are gamma globulins and have many if not
all the characteristics of antibodies — protein substances that provide
variable degrees of immunity to particular diseases. The presence of
such antibodies in rheumatoid arthritis presents the intriguing possibility
that there is some antigen present, some deleterious substance to which
the body is sensitive and to which it responds by producing antibodies.
To be sure, we have not yet been able to find the specific antigen, and
until we do, its existence must continue to be regarded as speculative.

There are many substances in normal body cells which could
possibly be antigenic. If they are in fact the antigens , then the
disease may result when some defect in body metabolism causes an over-
sensitivity to these normal substances. Another possibility is that
the substances might become antigenic only under certain conditions, or
after undergoing certain alterations.

Not too many years ago, classical immunological theory had no
place for such a concept as autosensitivity . We now know, however, that
auto sensitivity is indeed possible and have actually recognized it as
the cause of two diseases, one in which a person becomes sensitive to
his own thyroid hormone, and another in which one becomes sensitive to
his own red blood cells.

In the past several years the tempo of research in this area of
hypersensitivity has increased considerably, and more and more scientists
are becoming involved. Notable contributions have been made by
Dr. Henry G. Kunkel, a grantee of ours at the Rockefeller Institute, who

• 6 *
was the first to determine the exact size of the rheumatoid factor
molecules. The work of another Institute grantee, Dr. Morris Ziff , has
provided additional evidence supporting the sensitization theory.
Dr. Ziff has studied the families of patients with rheumatoid arthritis
and found that the rheumatoid factor occurs in many of the healthy
relatives of the patients as well as in the patients themselves, thus
suggesting that some hereditary metabolic defect is involved. The work
also suggests ; however, that a second abnormality is present, since not
all persons with the rheumatoid factor have clinical symptoms of the
disease.

In other Institute- supported studies of the rheumatoid factor,
scientists at New York's Hospital for Special Surgery and the Wilson
Research Foundation have found that the factor is produced in two kinds
of cells; plasma cells, present in the lining of human joints, and
''large pale cells" in the body's lymph nodes. This marks the first time
that the rheumatoid factor has been identified in human tissue.

There are many aspects of the problem that are indefinite, however.
Primarily> it is still uncertain that the rheumatoid factor is an antibody.
If it is an antibody, the specific antigen which causes its production
must be identified and it must be determined whether or not it is the
actual cause of the disease or merely a by-product.

These are the problems that confront us on the road of sensitization
research, as a possible cause of the rheumatic diseases. It is an
increasingly exciting road, but there is certainly no assurance that it

■- i ^:.">rr

7
is the right one. None the less, much of the recently uncovered evidence
strengthens the possibility that immunologic mechanisms are somehow
importantly involved.

Advances in Gout Treatment . The past ten years have also witnessed
major advances in the understanding and treatment of gout, another of the
rheumatic diseases. This ailment has plagued man for at least 4,000
years and affects approximately 30-.000 persons in this country. Usually,
the first sign of the disease is painful swelling in one of the joints
of the body } mere frequently than not that of the big toe. These attacks
of gouty arthritis generally subside after days or weeks, although they
recur at irregular intervals throughout the victim's life.

Associated, but in an unknown fashion, with these acute attacks
is a disturbance in body chemistry which results in an increase in the
amount of uric acid in blood and tissues. The uric acid is often de-
posited in cartilage, and in time forms large masses of chalky uric acid
salts. These deposits are known as tophi and may appear around almost
any joint.

The treatment of gout has centered around the use of two different

types of drugs, one type to overcome the acute attack of pain and swelling

and the other type to lower the uric acid concentration in the body. For

the acute attack, the most specific drug is colchicine, which has been

used for thousands of years. Several years ago Institute studies showed

r
that the drug is more promptly effective when injected rather than given

orally. It is also less likely to cause undesirable gastrointestinal

effects when injected.

- 8 -

Steady improvements have also been made in the uricosuric drugs.,
those which are used in the long-term treatment of gout patients and
promote the urinary excretion of excess uric acid. Two of the most
potent ones now available are zoxazolamine and sulfinpyrazone, both of
which have undergone clinical testing at the Institute. These drugs are
not useful in treating the acute attacks and must be supplemented with
such a drug as colchicine. Used properly, however, they are of great
value in preventing crippling.

Basic research in gout has now shown that the primary metabolic
defect in many gout patients is the overproduction of uric acid. This
has been a controversial question for many years, since the excess acid
might also have resulted from insufficient destruction of the substance
within the body, or the inability to excrete it in proper quantities.

Institute studies with an experimental drug known as DON indicate
that it may be possible to slow down the body's overproduction of uric
acid by drug therapy. The experimental compound blocks an enzyme needed
by the body for the synthesis of uric acid. At present, the drug has
little practical value since it causes undesirable side effects, but
it demonstrates that excess uric acid production can be reduced.
Research is continuing on similar drugs which will duplicate DON's action
without causing any ill effects.

DIABETES

A Problem in Basic Research . The greatest single achievement in
the study of diabetes was undoubtedly the discovery of insulin, an- event

- 9 -

v/hich took place long before the Institute was established. To
appreciate its importance, one has only to remember that prior to the
first use of insulin in 1922 the disease in its more serious forms
proceeded almost inevitably into acidosis, coma and death. Today . the
life expectancy of the diabetic is almost as long as that of the non-
diabetic.

As has been discussed previously with this Committee, diabetes is
probably the best known and most important of the metabolic diseases.
It results from either an insufficient production of insulin by the
pancreas, or from interference with insulin's action after it has been
produced. Because of this abnormality, the diabetic patient is unable
to properly utilize sugar (glucose) and excess amounts of it build up in
the blood and spill over into the urine. It is an extremely complex
disorder which is now known to encompass alterations in fat and protein
metabolism as well as sugar metabolism,

For many years researchers have been attempting to clarify the
exact manner in which insulin acts, as well as determine the specific
tissues upon which it acts. Within the past decade it has become
increasingly certain that one of insulin's most important functions is
to stimulate the transport of glucose across cell membranes, so that
energy- containing glucose can enter the cell from the outside.

Recent studies by Institute grantees at Harvard Medical School
suggest that fat tissue, far from being merely an inert storage side of
body fats, may be an important site of insulin action. Fat tissue taken

lie:'

- 10 -

from rats was found to be extremely sensitive to small amounts of the
hormone. The addition of insulin made the rate of sugar metabolism
increase six times in the tissue , apparently by making more extracellular
glucose available for intracellular metabolism.

It has also been demonstrated that insulin exerts a clear cut
effect on protein and fat metabolism which is exclusive of its effects
on glucose transport. An Institute grantee at the University of Chicago
has shown that insulin can influence protein synthesis within the cell
by a mechanism which is independent of the passage of either amino acids
or glucose into the cell.

There is still much to be learned about basic mechanisms that are
operating in this common metabolic disease. More research on the spatial
configuration and function of insulin is needed > and because of many inter-
relationships, the biochemistry and metabolism of other regulators--
especially the hormones of the pituitary and adrenal glands — must be
further investigated.

The Cli nic al Problem. Though the discovery of insulin still ranks
as the most important medical advance in diabetes, the recent widespread
use of the new oral antidiabetic drugs has brought about major changes
in the treatment of thousands of diabetics, freeing many of them from
daily injections of insulin. It is estimated that nearly a third of all
known diabetics are now using these drugs which can lower the level of
blood sugar.

In June 195? after widespread clinical tests, the first of these
oral hypoglycemic agents- -tolbutamide (Orinase) -became available to

l.:.- Li I

- 11 -

physicians, and thousands of diabetic patients found new freedom from
the discomfort and inconvenience of regular insulin injections.
Unfortunately, tolbutamide was not effective in all cases, particularly
those with severe diabetes and the juvenile or "brittle' 1 type of diabetes.

The second clinically-tested drug of this type appeared on the
market in October 1958. This was chlorpropamide (Diabinese) which is
slightly more potent and is excreted less rapidly than tolbutamide. These
two drugs were followed by two others, phenformin (DBI) and metahexamide.
The use of the latter one has now been discontinued because of its high
incidence of undesirable side effects.

Although the oral drugs possess one of insulin's major character
istics, the ability to lower blood sugar, they are not identical in
action to insulin, as it is usually administered. The most widely held
theory is that the drugs stimulate the beta cells of the pancreas to
release the natural store of insulin. But the complexity of the problem
is indicated by the fact that the drugs seem to have other actions as
well, such as the inhibition of the enzyme insulinase which naturally
destroys insulin.

One of the most exciting possibilities for the new oral drugs lies
in the field of diabetes prevention.

It has been reported to the Committee in previous years that a
great deal has been accomplished recently in the diagnosis of early
diabetes or "pre-diabetes" and in predicting, for certain population groups
and even for individuals the above normal likelihood of developing the

- 12 -
disease. Women who have given birth to extremely heavy babies and
children whose parents are both diabetic are almost certain to develop
diabetes. Persons without the usual symptoms of frank diabetes but with
a somewhat abnormal glucose tolerance curve have been shown to have an
eight times normal probability of developing the full-blown disease.
Brothers and sisters of diabetics apparently particularly those who show
abnormal glucose tolerance by a special test (the so-called ''cortisone
test' 1 ) are more likely to become diabetic than the average. These dis-
coveries make it possible to define and study individuals and population
groups who might be termed ''diabetes susceptible."

Using a small group of such individuals, grantees at the University
of Michigan have tested the glucose tolerance curves before and after
long-sustained treatment with an oral drug and have demonstrated some
improvement in these curves. It is as yet much too early to determine
the precise significance of these results but it makes imperative longer
term and more thorough observation of the possible effect of the oral
drugs on the development of diabetes in susceptible individuals.

"/ith such studies as these there has been an acceleration of
interest in diabetes and in diabetes research. This is a tangible and
certain result of the adventitious discovery of the effect of the new
oral drugs on blood sugar level.

BASIC RESEARCH - METABOLISM

Nobel Prize "./inning /fork on the Nucleic Acids . Cne of the most
outstanding achievements in basic research during our first ten years has

•l«ffl?

C&&1-

- 13 -

been the enzymatic synthesis of the nucleic acids, the chemical substances
inside the cell that are believed to control hereditary characteristics.
I am happy to report that this year a former chief of one of the Institute's
research laboratories, Dr. Arthur Kornberg, who is no\^ at Stanford University
and a grantee of ours, Dr. Severo Ochoa of New York University, received
the 1959 Nobel Prize in Medicine for their discoveries of the mechanixm
for the biological synthesis of ribonucleic acids (RNA) and deoxyri-
bonucleic acids (DNA) .

These two acids, DNA and RNA, are found in the nucleus of all
cells and are believed to be the information centers within the cell.
Depending upon the exact molecular structure of its nucleic acids, the
cell performs various functions, and when it divides to form two cells
seme of the original nucleic acids go into the new cell. This trans-
ported nucleic acid material then orders the new cell to develop and
function in the same manner as its parent.

Since the human body contains many different types of cells, each
type performing different functions, the molecules of DNA and RNA in
these cells must also be different and thus provide for the differentiation
of cells into organs and then into whole plants and animals. The nucleic
acids also control the development of species and individual character-
istics, and thus provide for hereditary continuity. Defects in these
nucleic acids, when they are transmitted from parent to child, are believed
to be the cause of many hereditary or familial diseases „

- H -

Because of their great importance, the Institute has emphasized
basic studj.es of the nucleic acids for the past several years, and the
Committee may recall my mention of this work in past reports. In 1957
we reported the first enzymatic synthesis of the nucleic acids by
Drs, Kornberg and Ochoaj ranking it as an outstanding achievement of that
year. Last year, we reported that although these studies cannot be
related to any given disease in man, "nevertheless, it can be stated
with some assurance that the information derived from these studies will
affect profoundly the whole future course of biological and categorical
research."

Ws are most happy that the Nobel Prize Committee has chosen to
honor Dr. Kornberg and Dr. Ochoa for their very important studies in
the nucleic acid field c

New Analgesic Marketed . Last year I reported to you that scientists
at the Institute had developed a new and potent synthetic pain-killing
drug that appeared to be superior to any natural or synthetic compound
then available, This year I am happy to add that extensive clinical
testing of the drug in more than 3,0^0 patients has confirmed our
expectations about the drug's usefulness and safety, and six pharmaceutical
companies have now been licensed to produce it in this country.

The new analgesic, which we identified as NIH 7519, was developed
by our section on analgesics and is the result of a program of basic
research in chemistry that began 30 years ago. The aim of this program
has been to produce a synthetic analgesic drug having a powerful

- 15 -

pain-killing action while at the same time being less addicting than
morphine. NIH 7519 has several important characteristics. It is approx
imately ten times more potent an analgesic than morphine, it is effective
in many cases of extreme pain that are not helped by morphine, and it is
comparatively free from such undesirable side effects as nausea, vomiting
and respiratory depression. Unlike morphine, the new analgesic can be
given orally , although its tendency to cause gastrointestinal disturbance
may limit its usefulness in this manner. Since it is a synthetic product
it frees the United States from dependency on the opium sources of the
world.

It should be emphasized that this drug is definitely habit-forming.
To be sure, it appears to be fulfilling its early promise in clinical
trials, in producing physical dependence somewhat more slowly and less
intensely than is the case with morphine. In considering its use ; however,
it must be kept in mind that it is addictive and must and will be controlled
under the narcotic laws. For the reasons stated earlier, it is nevertheless
an extremely useful and valuable drug.

The patent rights on the chemical process for synthesizing NIH 7519
have now been placed in the public domain and one of the six companies
licensed to produce it, Smith Kline and French Laboratories; at the first
of this year made it available to the medical profession under the trade
name Prinadol. Smith Kline and French Laboratories participated in the
development of the drug by providing experimental quantities of it for
clinical testing.

16 -

I mproved Treatment for Burn Cases . No review of our first ten
years of progress at the Institute should fail to mention the very
impressive work that has been done by a group of our scientists studying
burn shock and its treatment. The basic laboratory work, which began
at the Institute in 1942. has been extended over the years to include a
large-scale clinical study that promises to provide a more effective
therapy for severely burned patients not only in the prevention of death
from shock but also in successfully combatting later complications.

Burn shock usually develops three to five hours following injury
and accounts for a high proportion of the early deaths among victims of
burns covering 10 percent or more of the body area. The administration
of blood or plasma can often prevent or overcome this condition; but in
many areas of the world there are insufficient quantities of stored
blood to fill such needs. Major disasters in our own country could
seriously tax our supply of blood and plasma for emergency treatment.

Searching for a simpler treatment, the Institute scientists found
that in mice suffering from burn shock, the oral administration of a
solution of salt and soda was effective in preventing shock. The salt
and soda solution was then tested in human burn patients and found to
greatly reduce the number of deaths from shock that followed severe burns
This form of treatment would be of inestimable value in the event of a
large-scale catastrophe where intravenous therapy v/ould be impractical
and adequate supplies of blood or plasma probably would not be available.

17 -

The study then expanded when the clinicians treating the burn
victims noticed that many of them would appear to recover from the shock
period immediately following the burn only to succumb to a lethal
infection. Blood cultures showed that the infection was caused by an
organism called Pseudomonas, which was resistant to common antibiotics.
The problem was then brought back to the laboratory where attempts were
made to infect experimental animals with the Pseudomonas for research
purposes. These attempts failed until the scientists administered
cortisone to the animals to simulate the stress of burning. Animals
treated in this manner could then be infected with the organism and the
search began for a suitable treatment.

The first effective agent found for combatting the infection in
experimental animals was gamma globulin, the blood fraction that contains
antibodies. Preliminary trials suggested that this might be a valuable
therapeutic agent in humans as well. A form of treatment developed later
is the use of a specific antiserum to the Pseudomonas organisms. Pre-
liminary observations indicate that this may be even more effective
than gamma globulin.

This research achievement points up the interdependency of basic
laboratory work on the one hand and clinical investigations on the other,
and illustrates the benefits that accrue from such a dual approach.

FISCAL YEAR I960

Due to the support of this Committee and the generous increases in
the National Institute of Arthritis and Metabolic Diseases appropriation

- 1€ -
voted by the Congress , we have been able to strengthen very greatly the
research and training programs in all of our areas of responsibility.
In particular, we have greatly intensified our efforts in cystic fibrosis
and in gastroenterology and have initiated a program in civilian nutrition
surveys.

CYSTIC F IBROSIS

A Vigorous New Effo rt. An increasing proportion of the efforts
of this Institute is being exerted in research on the extremely important,
relatively new disease, cystic fibrosis. Recognized as a separate disorder
only 20 years ago, cystic fibrosis is a hereditary disease of children
and adolescents in which there is a generalized malfunctioning of mucus,
sweat and related glands, leading to recurring pneumonias undernutrition
and difficulty in withstanding the stressing effects of heat. The
significance of the expanding effort in cystic fibrosis research becomes
apparent when one realizes that this disease is responsible in the pediatric
age group for the majority of patients with chronic lung infections, nearly
all cases of pancreatic insufficiency and for about one-third of the
children with cirrhosis of the liver.

The Institute at Bethesda has taken the step of acquiring one of
the outstanding investigators in this field ; Dr. Paul A. di Sant'Agnese
of Columbia University. This scientist, who is also a qualified pediatric
specialist, developed the "sweat test" which has become the generally
accepted method of diagnosis for cystic fibrosis and has enabled many
cases to be detected which would otherwise have gone unrecognized. His

finding that patients with this disease excrete an abnormally high content
of salt in their sweat is the basis for this simple , reliable and very
important diagnostic test. In collaboration with biochemists he has
helped to uncover the chemical abnormality of mucus composition in patients
which seems to account for its excessive viscosity and reasonably explains
the pulmonary pancreatic and hepatic symptoms of cystic fibrosis. Much
more remains to be done, however, in the biochemical and physico-chemical
characterization of the abnormal mucus before a fully effective means is
likely to be found for dealing with it therapeutically. Dr. di Sant'Agnese
will direct the efforts to solve this fundamental problem by chemical
isolation and fractionation of the mucoids in bronchial secretions, in
duodenal juice and in saliva and by testing the action on these secretions
of varying concentrations of electrolytes, drugs and enzymes. Clinical
studies will also be pursued to characterize more precisely the abnormalities
in sweat electrolyte secretion in patients with various degrees of severity
of the disease; by measuring the behaviour of sweat salts in these patients
under various hormonal and dietary stimuli it is anticipated that much
more will be learned about the genetically controlled but as yet unknown
metabolic or enzymatic defect responsible for the disease.

Since the involvement of the lungs with chronic, recurring infections
dominates the clinical picture in the patient - the severity of this
involvement determines his fate - therapeutic study of this aspect of
the disease is considered most important. Investigators of the National
Institute of Allergy and Infectious Diseases are carrying on studies of
this aspect of the disease.

- 20 -

Support of research in cystic fibrosis through research and
training grants is also being steadily extended. Currently 38 investiga-
tive teams are being aided by the extramural programs of this Institute,
approximately double the number supported in the last fiscal year.

Progress made to date in research in cystic fibrosis has extended
the life span of patients through improved antibiotic agents and has
revealed increased numbers of patients through formulation of a specific
diagnostic test. These developments have served to outline the magnitude
and scope of the problem. The phase now being entered — with vigor — is
one of determining the underlying defect and resulting mechanism of disease
in the patient. Accomplishments during this phase should have profound
effects on the health of cystic fibrosis patients.

GASTROENTEROLOGY

Subst antial Progress in a New Field. Research in gastroenterology
is just beginning to feel the impact of the Institute's expanded program
of support, but substantial contributions have already been made in this
long-neglected field. More and more investigators are becoming interested
in the diseases of the digestive system (peptic ulcer, ulcerative colitis,
ileitis and others) and new research techniques have been developed. At
the present time the Institute is supporting 227 active research grants
in this area and 39 active training grants.

At our own facilities in Bethesda we have established the nucleus
of a new gastroenterological unit and have begun intensive studies of the
diseases which are grouped under the term "malabsorption syndrome."

- 21 -

These diseases are ones in which the absorptive capacity of the small
intestine has been affected. One of the primary aims of the new unit is
to apply our new knowledge of biochemistry to the study of the digestive
organs, investigating the metabolic processes that transpire in the cells
lining the stomach, intestines and gall bladder so that these processes
can be related to physiological activity. We are hoping to pinpoint any
biochemical abnormalities that may be present in these diseases and to
determine what effects these abnormalities may be having on the function
of the digestive organs.

Studies are also being done on the hereditary diseases of the
gastrointestinal tract, some of which resulted in impaired digestion
through interference with the function of the liver. Institute scientists
are attempting to detect hitherto unsuspected biochemical lesions that
may be genetically controlled and that may be causing some of these
familial diseases.

During the past year Institute- supported research has produced a
growing number of substantial contributions, some of which are readily
applicable to the treatment of the diseases themselves and others which
provide more fundamental knowledge about organ function and biochemistry.
Grantees at the University of Chicago have developed a method for producing
a condition in animals that resembles ulcerative colitis in humans. The
experimental colitis is produced by an immunological technique and lends
some support to the belief that ulcerative colitis may involve some type
of antigen-antibody reaction, although the evidence is still not conclusive.

"o.:<-

- 22 -

Physicians at the University of California School of Medicine have
developed an effective treatment for ammonia intoxication, a condition
that occurs when the liver becomes damaged by disease and can no longer
prevent ammonia from accumulating in the blood. They found that injections
of the amino acid arginine would bring about a prompt reduction in blood
ammonia levels, thereby preventing the serious neurological damage that
would otherwise occur.

CIVILIAN NUTRITION SURVEYS

For the past several years we have participated with the Department
of Defense, the State Department, the Department of Agriculture, the
Atomic Energy Commission and the International Cooperation Administration
in the activities of the Interdepartmental Committee on Nutrition for
National Defense. Under this sponsorship, and at the invitation of the
countries involved, studies have been made of nutritional conditions in
Iran, Pakistan, Korea, the Philippines, Turkey, Libya, Spain, Ethiopia,
Peru, Ecuador, Vietnam, Chile and Colombia, with particular attention to
the nutritional status of their military manpox^er. Where indicated,
corrective measures were suggested by our survey teams and initiated by
the countries. Excellent results have been achieved.

It has been deemed highly desirable to extend these studies to
civilian populations and a number of requests for such surveys have
been received by the Secretariat of the Interdepartmental Ccmmittee on
Nutrition for National Defense from official agencies in countries in
various parts of the world. During the present fiscal year, with funds

- 23 -

allocated from the I960 budget, collaborative arrangements have been
initiated with Naval Medical Research Unit 3 for intensive clinical and
laboratory studies of civilian populations in Egypt and in the Sudan.
Follow-up studies and analyses of survey findings in both military and
civilian populations are being conducted in Ethiopia, Vietnam, Chile,
Colombia, and Ecuador.

SUMMARY

The first ten years of the National Institute of Arthritis and
Metabolic Diseases have been a period of steady growth in a well-planned
program to increase the effectiveness of national medical research. This
program has been enhanced through the support of increased efforts by
Institute scientists in Bethesda, by expanding support of research project
grants to scientists throughout the country and by stimulation of the
training of growing numbers of much better qualified investigators through
training grants and fellowships.

The decade has seen aolid research accomplishments in the fields
of medicine and biology in which this Institute is so deeply interested —
in the chronic diseases, arthritis, gout, diabetes, endocrine and
metabolic disorders, and in the broad fundamental disciplines of bio-
chemistry, nutrition and metabolism. More recently valuable accomplishments
have been made during the course of the emergence and development of
(a) studies in the genetically controlled molecular diseases, (b) germfree
techniques for the study of nutrition and metabolism, (c) international
research programs involving nutritional surveys of civilian populations

Jr.-

- 24 -

and the investigative-epidemiologic approach to the study of many diseases
throughout the world,, and (d) the new broad discipline of physical biology.
Current vigorous expanding efforts are being exerted in the relatively
young field of research, gastroenterology and in the relatively new
disease, cystic fibrosis.

In conclusion, Mr Chairman, the appropriation request for 1961
is a total of $47,541,000 as compared with the appropriation of $46,862,000
for I960. This allowance for 1961 will provide for the continuation of
I960 program levels in all activities and will permit some increase in
grants for research projects and minor increases in direct research
activities, principally in cystic fibrosis, gastroenterology and nutritional
research under germfree conditions. This request for 196l is distributed
among program activities as follows:
Grants :

Research projects 132,153,000

Research fellowships 437,000

Training grants 6,298,000

Direct research and supporting services 8.653.00

Total 47,541,000

SUMMARY OF OPENING STATEMENT

Director, National Institute of Neurological

Diseases and Blindness

Public Health Service

COMMITTEE ON APPROPRIATIONS
1961 ESTIMATE
for
'Neurology and Blindness Activities'

Mr. Chairman and Members of the Committee:

In reviewing the progress of research and training relating
to the brain and central nervous system, a number of areas may be
poinded out which hold special promise for the future.

It is now generally recognized that neurological and sensory
disorders constitute the primary cause of lifelong crippling in
the United States and rank third as the cause of death. New
statistical data emphasize again the extent to which long-term
disability is caused by neurological disorders and stress the
importance of the prenatal, birth, and early life period of
development.

In view of this vast problem, a major attack has been made
in this area by the Institute through its Collaborative Project
on Cerebral Palsy, Mental Retardation, and other Neurological
and Sensory Disorders of Infancy and Childhood. The project is
now completing its first year of study after two and a half
years of intensive preparation. Approximately 5500 mothers and
4200 babies were studied in the pretest phase and 3300 mothers and
1300 babies had been studied as of October 1 in the final study

- 2 -
series. Early reports from the collaborating institutions hold
many hopeful developments.

Through important advances in our knowledge of the bio-
chemical defects of mental deficiency, galactosemia and phenyl-
ketonuria can both be ameliorated by special diets. Also
a simple mass screening test for phenylketonuria has been
developed. Through the examination of special preparations in
tissue culture it has been found that Mongolism is attributable
to a chromosome abnormality which probably develops at the time
of ovulation.

Continued research at the Bethesda Clinical Center has
further demonstrated this year the effectiveness of surgery in
selected cases with temporal lobe epilepsy. In experimental
studies in neurochemistry, attempts are being made to alter the
level of gamma- aminobutyric acid in the brain to determine the
effect of this change on seizure activity. Investigators also
demonstrated hyperactivity in single cells in epileptic tissue.

The most dramatic accomplishment in the past few years in
the field of neurosurgery has been the application of hypothermia
to brain surgery. This procedure has proven especially valuable
in the treatment of intracranial aneurysms. The Institute's
cooperative aneurysm project is now evaluating and refining the
surgical approach to this problem and much of the success of this
study is attributable to the new surgical techniques.

This year the Institute has laid the groundwork for a new
epidemiological program to determine variations in the incidence

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- 3 -

and character of cerebrovascular diseases in different countries.
Recent epidemiological studies relating to sclerosing disorders
have already demonstrated a peculiar geographic distribution of
multiple sclerosis and variations in background cosmic radiation
at different latitudes are now being studied. Applying the
methods of epidemiology to the study of Parkinson's disease
promises new information on the occurrence of this crippling dis-
order in many countries.

During the past year, attention has been given to the
regeneration of muscle in certain muscle disorders. Scientists
at the Institute have successfully evaluated the anticholinesterase
activity of drugs widely used in treating myasthenia gravis and
are testing the effectiveness of newer, potentially useful com-
pounds .

During the past year there has been a continued shift of
emphasis in the total research grants program, particularly in
the area of sensory disorders. Three years ago the Institute had
no research grants relating to disorders of speech; this year it
is estimated there will be 22. There also has been a rapid
growth in grants relating to hearing and vision — an estimated
74 this year in disorders of hearing and 278 in disorders of
vision.

This rapid increase in not only quantity but quality of
research projects is a direct result of the Institute's training
program. During 1960, there will be approximately 190 training

- 4 -
programs in all neurological and sensory areas providing training
for 9 30 trainees. Of the 930 individuals in training, a little
less than one-third, or about 300, will complete training this
year.

Many scientists now believe that international studies
could hasten the answers to unsolved neurological and sensory
disorders. With this thought in mind, the Institute has estab-
lished an office for international neurological research programs
in Antwerp, Belgium, under the direction of Dr. Pearce Bailey,
the Institute's former director. Dr. Bailey's liaison capacity
with the World Federation of Neurology and its professional
societies in more than forty countries will aid the Institute
in surveying and evaluating international neurological talent
and facilities throughout the world.

In conclusion, Mr. Chairman, the appropriation request
for 1961 is a total of $39,662,000 as compared with the ap-
propriation of $41,487,000 for 1960. This allowance for 1961
will provide for the continuation of the 1960 program levels
in all activities and will permit some increase in grants for
research projects. It is distributed among program activities
as follows:

Grants ;

Research projects -- $24,221,000

Research fellowships 536,000

Training 7,339,000

-■•Tii- Ci

- 5 -
D irect Operations :

Research 6,371,000

Review and approval of grants 934,000

Training activities- 50,000

Administration 211,000

TOTAL - 39,662,000

OPENING STATEMENT
by
Director, National Institute of Neurological Disease- and Blindness

Public Healch Service

COMMITTEE ON APPROPRIATIONS
1961 ESTIMATE
for
"National Institute of Neurological Disease^ and Blindness"

Mr. Chairman and Members of the Committee:

It is a pleasure for me to appear before thio Committee for
the first time as director of the National Institute of Neurological
Diseases and Blindness. Dr. Pearce Bailey, who has been the direc-
tor of the Institute since its founding, is now in charge of the
Institute 1 , International Neurological Research Programs with
offices in Antwerp, Belgium. He will serve in a liaison capacity
with the World Federation of Neurology and as an advisor to the
National Institutes of Health on international neurological programs,

My scatement will review for the Committee progress in re-
search and training relating co the brain and central nervous system
and point out areas which hold special promise for the future.

The brain is the most complex structural organization known
to man. The population of cells of the brain is four times the
human population of the earth. The integrated performance of this
community of nerve cells is based upon functional and structural
organization which has surpassed understanding. Although the brain
has aroused unusual curiosity through the centuries, the magnitude
of its complexity, inaccessibility, and inviolability has delayed
scientific investigation.

- 2 -

Abouc seventy-five year^ agu there was a period oL unusual
optimism concerning brain research. New techniques had been
discovered which made it possible to carry out accurate micro-
scopic studies of the brain. In addition there was a large
unexplored field for the clinical description of disease. This
period of extensive advance ended a„ the contributions of these
techniques became exhausted, and there followed a period of
inactivity and stagnation.

Since the war, new techniques of neurophysiology and neuro-
cheinistry, together with the use of the electron microscope and
implanted electrodes, have again encouraged research in this long
neglected area. Unfortunately, trained personnel were not im-
mediately available to exploit these new opportunities. There-
fore, when this Institute was created by Congress in 1950, its
responsibility was not only to stimulate and conduct research
relating co the brain and central nervous system, but to train a
sufficient number of teachers and research scientists to supply the
need .

The magnitude of the neurological problem, the degree to which
impairment is suffered before and at birth, and the extent of life-
long disability have been underlined recently by new scatistics. The
1956 amendments to the Old Age and Survivors Insurance broadened the
program to include seriously disabled children aged 18 and over. It
has been found that 94 percent of these benefits have been paid to
persons with neurological disorders and only 6 percent to persons
with other disorders. The figures also show that 75 percent of all

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- 3 -
these disabled individuals suffered their impairment at or prior to
birth. The amendments, of course, have L>een in effect only a short
period of time tut there is no evidence to indicate that percentages
will change as the number of persons in the program increases.

For some time it has been recognized that neurological and
sensory disorders constitute the primary cause of permanent crippling
in the United States and rank third as the cause of death. The new
figures emphasize again the extent to which long-term disability is
caused by neurological disorders and stress the importance of the
prenatal, birth, and early life period of development.

Because researchers are convinced that conditions existing
during the early periods of life are responsible for a large percentage
of disabilities which may continue throughout life, a major attack has
been made on this area by the Institute. The Collaborative Project
on Cerebral Palsy, Mental Retardation, and other Neurological and
Sensory Disorders of Infancy and Childhood is now completing its first
year of study after two and a half years of intensive preparation.
Approximately 5500 mothers and 4200 babies were studied in the pre-
test phase and 3300 mothers and 1800 babies had been studied as of
October 1 in the final study series.

The early reports from the collaborating institutions hold many
hopeful developments. For the first time, representatives from various
disciplines across the nation are usin uniform protocols to follow
in detail developments of pregnancy, labor, delivery, and early infancy.
During the past year, a protocol for the examination of the placenta

- 4 -
was de /eloped and a manual for placental examination prepared, a
protocol also was developed for the neurological examination of the
newtorn infant and a training film demonstrating the technique of the
examination completed. A procedure for collection of blood specimens
from the pregnant woman for virus studies has been established and
specimens from patients are being carefully filed in a newly equipped
coldroom. As a result of these and other developments , a well-rounded
total program is evolving. In the broadest sense, its objective is
to evaluate those factors influencing the health of mothers and children
throughout the nation.

CHRONIC NEUROLOGICAL DISORDERS OF CHILDHOOD AND ADOLESCENCE
Of all the chronic neurological disorders of childhood and
adolescence, mental retardation and cerebral palsy affect the most
li^es. Of the 4,200,000 children born each year, 126,000 have some
form of mental subncrmality . Approximately one -third of the four and
a half million mentally retarded persons in the nation are children.
In relation to cerebral palsy, it is estimated that $216 million is
required annually for some 360,000 patients who require special care.

The past five years have seen important advances in our knowledge
of the biochemical defects of mental deficiency. The fact that
galactosemia and phenylketonuria can both be ameliorated by special
diets has provided increasing incentives and hope in the search for
other similar anomalies. The newly discovered Hartnup's disease and
"maple sugar" disease may also be amenable to dietary treatment.

- 5 -

During the past year, a simple mass screening cet>t for
phenylketonuria has been developed, and there is now no reason for
this important cause of mental deficiency to go undetected and bring
irreparable brain damage. At present, there are several simple diag-
nostic tests available. A chemical reagent added to a wet diaper,
the use of a diaper powder, or the use of impregnated paper, quickly
shows an abnormal color when unusual amounts of phenylalinine are
present. In addition, a rapid blood test is now available which will
detect phenylketonuria as early as the fourth day of life. This is
particularly useful in the case of a sibling of a child known to be
affected by the disorder.

Recent reports emphasize the effective campaign against
kernicterus. Up until five years ago, kernicterus was responsible
for one percent of admissions to institutions for the mentally
defective. One institution reports that over the past three years
not a single case of mental retardation or cerebral palsy attributa-
ble to kernicterus has been admitted.

One of the most important discoveries of the last five years
relates to abnormalities of human chromosomes. It is now possible
to observe these abnormalities through the examination of special
preparations in tissue culture. This technical advance has demon-
strated that Mongolism is attributable to a chromosome abnormality
which probably develops at the time of ovulation. In addition to
Mongolism, several other forms of mental deficiency have been found
to be due to similar chromosomal defects.

- o -

Since the sex chromosomes are easily identifiable and their
aberrations have been readily detectable, the major emphasis to
date has been on forms of mental retardation associated with abnor-
malities of sexual development. The new techniques, however, should
make possible the demonstration of similar abnormalities in other
chromosomes. It is possible that additional forms of mental retarda-
tion will be found to be attributable to similar abnormalities.

The importance of severe hypoglycemia in the first few days
of life is again assuming great importance. Especially in instances
in which mothers have experienced toxemia during pregnancy, there
appears to be a tendency for a sudden severe fall in blood sugar
levels in their infants. This is often associated with convulsions
and may lead to permanent brain damage, mental deficiency, or cerebral
palsy of the child. This condition of low blood sugar is readily con-
trolled but requires the continuous administration of intravenous
sugar over a rather long period of time. The recognition of the
importance of this factor is imperative if these children are to be
spared irreversible damage.

A number of significant studies are being conducted to de-
termine those factors during pregnancy which influence the welfare
of the offspring. There is now evidence to show that variations in
the maternal blood proteins may be correlated with the outcome of
pregnancy. In nineteen patients in whom abnormal proteins were
demonstrated, approximately 79 percent had an abnormal pregnancy
outcome. It is not yet known whether the abnormal protein is

- 7 -
related to some intoxication, abnormality of dietary intake, or
constitutional deface of the mother.

The importance of diabetes as a factor in the production of
brain damage in infancy has been ably demonstrated over the past
five years. Most recently it has been determined thac even a mild
degree of maternal diabetes may influence the outcome of pregnancy.
The likelihood of such "pre-diabetes" can be detected from the
physical characteristics of the mother and can now be affirmed by
glucose tolerance tests during pregnancy.

In recent years, damage to the fetus has been pinpointed to
the time of prenatal infection. In the case of rubella, evidence
suggests that proper use of immune globulins may prevent fetal dam-
age. The final solution in this instance, however, depends upon
the development of specific immunization for this disease.

Last year it was reported that perinatal infection could be
demonstrated promptly by placental examination and early treatment
of the affected child. Recent placental examinations indicate that
premature degeneration of this organ may be one of the factors
responsible for prematurity. (Prematurity has been indicated as
a serious factor in cerebral palsy and mental retardation.) Ab-
normalities of certain blood chemical constituents may provide a
clinical clue to the occurrence of such placental degeneration
during pregnancy.

Hydrocephalus, an excess of fluids within the skull, with
resulting expansion of the cavities of the brain, compression of

- 8 -
the brain tissues, and an enlargement of the head, is another cause
of mental deficiency and cerebral-palsy. Advances in neurosurgical
techniques are providing new means for bvpassing points of obstruc-
tion, permitting outflow of fluid and relieving the pressure. The most
recent development is the perfection of a small ball valve which can
' e placed in a tube entering one of the veins of the chest and allows
fluid drainage into the blood stream. The ball valve prevents the
Lack flow of blood and contamination of the spinal fluid. Another
effective technique is the use of a long tube to connect the spinal
fluid spaces with the abdominal cavity within which absorption of
fluids can take place.

EPILEPSY

A conservative estimate regarding the total cost of epileptics
to the nation is probably/ more than $80 million annually. New medical
and surgical treatment now available make it possible for more than 50
percent of the nation's million and a half epileptics to have their
seizures controlled. The majority of these are capable of employment
but various laws and outdated thought concerning, the disorder make
employment opportunities difficult to find.

Epileptic seizures result from many different conditions. Some
of these are associated with actual brain injury and others with inter-
ference with the brain's normal chemical reactions. This past year
research directed toward the sur ical and medical control of epileptic
seizures has increased at the Bethesda laboratory and through grants
at many medical centers throughout the country.

t. si:"!

- 9 -

Continued research at the Bethesda Clinical Center has further
demonstrated this year the effectiveness of surgery in selected cases
with temporal lobe epilepsy. These studies are concerned with the
removal of damaged parts of the brain functioning abnormally. This
past year, a numfear of cases coming to surgery showed a Lony deformity
of the middle fossa which protruded through the dura into the brain.
This deformity was not evident in the preoperative examinations and
the cause is not clear.

Medical studies, chief ly chemical, are being pursued to determ-
ine the extent to which abnormal substances in the brain may be the
cause of seizures. This research also may show how the irritant
effects of such substances might be altered by dru^ therapy.

Studies in neurochemistry have revealed that gamma-aminobut^ric
acid, present in relatively large amounts in the normal brain, may
regulate a portion of the available energy and affect levels of
functional activity within the brain. Attempts are bein^ made to
alter the level of this compound to determine the effect of this
change on seizure activity.

In another study, a compound capable of producing seizures
was given to mice. The investigators later succeeded in finding a
compound which corrected the abnormalities causing the seizures.

Investigators have also demonstrated hyperactivity in single
cells in epileptic tissue. These findings further support the theory
that abnormally increased activity in nerve cells is the fundamental
defect of tody action in epilepsy.

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- 10 -
NEUROSURGERY

One of the most important developments of the past five years
is the improvement of techniques for neurosurgical intervention. In
intracranial surgery, the surgeon must operate within a very nar-
rowly confined space and the operation is slow and tedious. Even a
moderate amount of bleeding may seriously interfere with his ability
to proceed. In addition, the brain is subject to rapid swelling
which again may block the work.

The first step forward was the development of new anesthetic
and muscle -relaxing agents which made it possible to operate with
very low levels of anesthesia--and often in the semi-conscious
state. The next achievement was che development of drugs capable
of lowering blood pressure. These contributed greatly to reducing
hemorrhage in surgical procedures.

The most dramatic accomplishment, however, has been the
application of hypothermia to brain surgery. When the body is arti-
ficially cooled, the need of the brain for oxygen is materially
reduced, and the circulation can be interrupted for long periods of
time--even up to fifteen minutes. This procedure has proven es-
pecially valuable in the treatment of intracranial aneurysms --the
sac-like dilations of the blood vessels which are subject to rupture
and often cause death. The Institute's cooperative aneurysm pro-
ject is now evaluating and refining the surgical approach to intra-
cranial aneurysms. Much of the success being demonstrated in this
study is attributable to the new surgical techniques.

'-"!

- 11 -

The use of hypothermia may also prove to be of value in
cases of head injury, Severe swelling of the brain following
head injury leads to further damage in the post injury period.
Animal experiments have demonstrated that moderate degrees of
hypothermia reduce the brain's need for oxygen during these
critical periods * In addition, hypothermia may reduce the leak-
age of fluid from the blood vessels and thus keep down pressure*

An important new development in this area is a technique
through which the blood for the brain may be coded without the
necessity of cooling the entire body. In this way the brain may
be relieved of its need for oxygen, yet the rest of the body may
be maintained in its normal state.

CEREBROVASCULAR DISEASES

The cost to the country in lost productivity and for the
care of more than one million Americans crippled by cerebrovas-
cular diseases is vast. Approximately 40,000 of the more than
175,000 deaths each year from stroke and related ailments are
in the working age group from 25 to 64 years.

During the past two years, data have been accumulating
in the two large cooperative projects concerned with preven-
tion of cerebrovascular diseases. On the study of aneurysms,
the reports are still not final. The initial results of the
anticoagulant study have revealed that the use of anticoagu-
lants does not produce a dramatic change in over-all mortal-
ity. Statistical analysis is not yet sufficiently complete to

' '. : .1

- 12 -
determine whether moderate improvement may or may not be accom-
plished by this iorm of therapy. This study, however, is pro-
viding information on certain benefits to be derived from this
therapy, its limitations, the types of cases in which therapy is
desirable, and the complications to be avoided.

Anticoagulants have been found effective in the treatment of
vertigo due either to impending thrombosis of the posterior inferior
cerebellar artery or to recurrent basilar insufficiency. Their use,
however, has been found difficult and sometimes hazardous and in-
dicates that long-term anticoagulant therapy should be used for
vertigo only if a good response to early treatment is obtained.

This year the Institute has launched a new epidemiological
program to determine variations in the incidence and character of
cerebrovascular disease in different countries. This study en-
visions comparison of changes observed in postmortem examination
of the brain in patients from many countries under varying
geographical and ethnic conditions.

SCLEROSING DISORDERS

One of the major American neurological problems deals with
the prolonged disability of patients with multiple sclerosis and
related demyelinating disorders. Voluntary health agencies in this
field estimate that there are 250,000 patients with multiple
sclerosis and pernaps another 250,000 with related disorders.

This year the publication of the reports of the conference
dealing with "The Biology of Myelin" represents a milestone in

- 13 -
development of our knowledge in this area. Kyelin--the protective
sheath which surrounds each of the axones--is one of the essential
building materials of the central nervous system. Destruction of
myelin is a key feature of multiple sclerosis and other dernyelinatino
disorders, and the rapid development of our knowledge of the chemical
and physical processes underlying its production is important to the
further understanding of these destructi/e processes.

The most important discovery in the biosynthesis of lipids
(fats) since the discovery of the mechanism of the formation of sphin-
gosine has been the finding that long-chain fatty acids are built by
a condensation of 3-carbon fragments, called malonyl coenzyme A.
Before carbon atoms from carbohydrates or proteins can become fats,
they must pass through this newly discovered intermediate stage.

Closely connected with the study of the formation of myelin
is the evaluation of "allergic encephalomyelitis" --the inflammatory
process through which the myelin is destroyed in certain allergic
conditions which have at least superficial resemblances to multiple
sclerosis. The method of production of this disease in animals has
now been well established, and this year brought further clarifica-
tion of the specific chemical fraction responsible for producing the
destructive reaction.

Important new investigations now su-gest that by proper
treatment with desensitizing fractions of nervous tissue, it may

- 14 -

be possible to modify the allergic reaction in the sensitized
individual and thus prevent the recurrent destructive episodes
which characterize the allergic encephalomyelitis state.

It is still uncertain what initial process may trigger
the sensitization which then leads to brain destruction in
conditions such as multiple sclerosis. A causative agent for
multiple sclerosis has still not been discovered, but increas-
ingly the finger points toward the possibility of some as yet
undetermined type of virus reaction^. Similarity of multiple
sclerosis to certain virus diseases of animals is under
investigation,

The important clue represented by the peculiar geograph-
ical distribution of multiple sclerosis continues to be investi-
gated. Our most recent epidemiological investigations demon-
strate, for example, that multiple sclerosis is over twice as
common in the colder climate of Halifax, Canada, as it is in
Charleston, South Carolina. This is not a racial factor but
apparently depends upon some geographic or climatic difference.
Once the disease is established, it has not been shown that
removal to a different climate influences its course.

There is some possibility that the differential incidence
associated with climate may be secondary to variations in back-
ground cosmic radiation found at different latitudes. This
question is now under study.

Studies conducted jointly by this Institute and the
Veterans Administration are providing information regarding the

- 15 -
life history of multiple sclerosis in individuals diagnosed as
having this disease during the war years. It has been demon-
strated that retrobulbar neuritis-- formerly thought to represent
a precursor of multiple sclerosis--eventuates in the full disease
in a relatively small percentage of cases, probably under 20
percent.

The Institute cooperated with the Danish Multiple Sclerosis
Society and the World Federation of Neurology's Commission on
Biometry and Genetics, to sponsor a Geomedical Conference on
Multiple Sclerosis in Copenhagen last June. The principal
theme of the conference concerned studies of the frequency of
multiple sclerosis in various geographic areas of the world and
the evaluation of current epidemiological techniques used in
geographic neurology.

NEUROMUSCULAR DISORDERS
Diagnosis and treatment of the various types of diseases
of muscle present one of the most complex neurological problems.
Generally these disorders fall within three categories: diseases
of the muscle itself, or muscular dystrophies, in which the
muscle tissue seems to be diseased or destroyed; disorders af-
fecting the muscle-exciting system and the initiation of muscle
contraction, such as myasthenia gravis and certain familial periodic
paralysis disorders; and inflammation of the muscle known as
myositis. Differentiation witl.vn the categories has been difficult.
Research during the year has resulted in advances in diagnostic
techniques.

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Muscle biopsy has proved to be an effective means of differ-
entiating certain types of neuromuscular disorders. Uith this
technique, a more exact diagnosis and earlier prognosis may be made.
In the case of some of these disorders, treatment may prove bene-
ficial if started early in the development of the disorder. Another
technique of great value in the diagnosis of muscle diseases is
electromyography.

During the past year attention has been given to the re-
generation of muscle in various neurogenic and primary muscle dis-
orders. An inclusive study of the primary pathology of peroneal
muscular atrophy has been concluded and the final studies of the
various inter-related factors in cationic paralysis have also been
concluded.

Scientists at the Institute have successfully evaluated the
anticholinesterase activity of drugs widely used in treating myas-
thenia gravis. By correlating this activity with the drugs' clinical
usefulness, scientists are establishing a basis for testing newer,
potentially useful compounds.

In addition, a new series of anticholinesterase drugs de-
rived from plants of the Amaryllis family may offer advantages in
the treatment of myasthenia gravis. Tests show that the antichol-
inesterase activity of these compounds ranges from equal to somex^hat
greater than drugs now in use to treat the disorder. However, ex-
tensive clinical trials will be necessary before the drugs are
admitted to general use.

- 17 -

INVOLUNTARY MOVEMENTS - -TREMORS AND SPASMS

While progress continues in surgical relief for involuntary
movements, the search for preventives and for medical control has
intensified lecause surgery apparently will never be a fully satisfy-
ing control method. In Parkinson's disease alone, an estimated
million and a half persons are afflicted.

Surgical methods for the relief of involuntary movements have
. een developed and refined during the last five years. Originally,
these were developed primarily for the relief of rigidity and tremor
in Parkinsonism . More recently, other bizarre forms of involuntary
movement and spasm have proven capable of relief by surgical measures,
Recently, injections of dru 6 s in precise areas of the brain and
surgical destruction of specific areas of the brain have been in-
vesti ated. The chemical studies are providing important information
re^ardin^ the methods through which areas of the Lrain controlling
movement may be activated b> chemical and mechanical means.

Neurochemists are participating in a two-pronged attack
on Parkinson's disease. More information on the brain centers
involved in tremor and rigidity, and detailed testin.j of possi-
ble medicines will help progress toward control. The discovery
that certain tranquilizing dru fo s produce Parkinsonism lends
added impetus to this approach.

The international application of the methods of epidem-
iology to the study of Parkinson's disease promises new informa-
tion on the occurrence of this crippling ailment in many countries.

- 13 -

ENCEPHALITIS

The outbreak of encephalitis in New Jersey this past
summer highlighted again the seriousness of this disease with
its high mortality rate and the large percentage of permanent
brain damage which follows the disorder. Many conditions cause
encephalitis or brain fever, and it is often difficult to de-
termine whether the cause is virus infection, allergic reaction,
or toxic and deficiency states.

This year more than fifty scientists from fourteen countries
met in Antwerp, Belgium, to discuss the neuropathology and patho-
physiology of the various encephalitides occurring around the
world. The conferees classified and defined the known types of
encephalitides so that a common language may be provided for the
exchange of information among researchers throughout the world.

PUERTO RICAN PROJECT
This year has seen the continuing favorable development of
the primate colony in Puerto Rico. There are now more than 260
healthy monkeys in the free ranging colony on Cayo Santiago.
Their physical and mental development in the free state is under
examination. In addition, the caged colony at the University of
Puerto Rico now has almost 100 breeding females. During the past
year these animals have contributed strikingly to our scientific
knowledge. Specifically, it has been possible to reproduce in
monkeys the complete picture of cerebral palsy v;ith striking re-
semblance to the human disorder. The mechanisms and nature of

TOv.

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- 19 -

; ;h\3 disability are now under further investigation.

This past summer, in collaboration with European investiga-
tors, epoch-making investigations of the oxygenation of the unborn
monkey were conducted. For the first time, accurate records of the
oxygen supply of the fetus were obtained, and these will have wide
implications for antenatal causes of fetal suffocation in the
human .

RADIATION EFFECTS ON CENTRAL NERVOUS SYSTEM
Aware of the desirability of developing new knowledge regard-
ing the possible effects on the nervous system of long-continued,
low-level radiation, the Institute initiated a new research program
in this area. Although a number of studies have been completed
which demonstrate the effects of a single large dose, there are
wide differences of opinion regarding the effect of long-continued
dosage on the nervous system. It has been demonstrated that even
moderate radiation dosages have some effect on the nervous system,
as indicated by alterations in tolerance to anesthesia, as well as
over-all effects on longevity. It is now necessary to determine
the effects of long-continued, low-level irradiation.

AGING
The Institute has placed an emphasis on the two extremes of
age -- the tragic neurological and sensory disabilities of children
which often continue as serious lifelong disorders, and the crip-
pling conditions of old age which shorten the satisfying period of

T---0

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- 20 -

usefulness. As the life span has lengthened, such disorders as
Parkinson's disease, cataracts, glaucoma, and cerebrovascular
diseases, mostly associated with later life, have loomed as larger
problems. Special attention, therefore, is being given to research
directly related to these disorders and to research on the aging
process of the central and peripheral nervous systems.

Institute and grant-supported investigators are currently
pursuing two major avenues: one assumes that the aging process
may be a natural pattern of growth; the other, that aging is not
inevitable or normal but rather that it results from repeated in-
juries or toxic reactions operating over a life span. Therefore,
a number of studies have been developed to determine alterations
in the physical and chemical structures of the tissues with aging.
Colonies of aging animals are being maintained in various centers
for research on such alterations in the aging process.

The proceedings of the symposium on aging, reported pre-
viously, have now been published and are proving to be a stim-
ulant for researchers in this field.

DISORDERS OF VISION
Research relating to the major blinding disorders, such as
cataract, glaucoma, uveitis, retinopathy, and ocular tumors, con-
tinued to progress this year. An estimated 70 million people in
the United States have some form of eye defect. Of these, a
third of a million are considered legally blind, including
35,000 children and 225,000 adults over 50 years of age. It has

V'Jji

- 21 -
been estimated that blindness costs this country over $500 million
a year. We now know that some 50 percent of all blindness can be
prevented, and this figure is increasing constantly as a result of
research and training efforts in this field.

An important cause of blindness in the older age groups is
glaucoma--a condition associated with increased pressure of fluids
within the eye a In most cases, this pressure is caused by an un-
known obstruction of the normal outflow of aqueous humor from the
eye. Thousands are blinded each year because glaucoma was not
detected in time, and, more important, there are an estimated one
million persons with undetected glaucoma.

For these reasons, the Institute, in cooperation with the
Bureau of State Services, has launched a 5-year cooperative study
to evaluate techniques currently used to detect and identify
glaucoma. The four participating institutions will concentrate
their efforts on developing methods of diagnosing glaucoma earlier
than present methods permit.

Related basic research is underway to measure the outflow
and formation of aqueous fluids in the normal and diseased eye, as
well as the factors which regulate the fluid pressure. The effects
of various drugs such as acetazolamide on relieving intra-ocular
pressure are also being investigated.

This year, Institute grantees have reported valuable new
techniques for diagnosing certain types of glaucoma. The results
of an 8-year survey show that the technique of tonography, where

«5.r

- 22 -
intra-ocular pressure is measured, offers criteria for early diag-
nosis of primary glaucoma. Another grantee study indicates that
certain tissues in the eye are damaged early in the course of
glaucoma and that therapy should decrease pressure to a point
where these tissues will escape damage.

Detachment of the retina is another cause of blindness. Years
ago, scientists found that this separation could be arrested if a
small surgical scar was produced, causing inflammation and adhesion
of the retina to the underlying choroid. A new method of sealing
these breaks has been devised where an intense light is focused on
the retinal surface. The scarring thus produced, without surgical
intervention, may seal the retina to the choroid and prevent fur-
ther detachment.

An outstanding development in the cataract program is the
demonstration of minute changes in the structures and fibers of
the cataractous lens. Using the electron microscope, investiga-
tors have found that cytoplasmic changes also occur early after
irradiation, which may lead to cataract formation.

A new project was initiated this year to evaluate the ef-
fects of alphachymotrypsin, an enzyme which facilitates the surg-
ical removal of cataracts. A result of this study has demonstra-
ted the process of cell division in the corneal epithelium. A
new and rapid method for producing experimental cataracts has also
been devised by Institute scientists.

Although little is generally known about treatments for

vr.

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- 23 -
uveitis, investigators have found that some of the resulting inf lam-
nation responds well to steroid therapy. Where uveitis is caused
by toxoplasmosis, therapy has been effective in 50 percent of
treated cases. More of these favorably reacting cases were under
age 20 with an acute or subacute course. Older chronic cases
reacted less favorably.

DISORDERS OF HEARING AND SPEECH

Hearing impairment is a major cause of difficulty in speak-
ing and understanding language and it is estimated that there are
some 15 million Americans with hearing defects. Approximately
415 million of these are seriously handicapped by deafness, and
about 760,000 are totally deaf. In addition, from two to five
percent of American children between the ages of 5 and 20 have
speech disorders which interfere with normal development. Because
so many are afflicted with speech and hearing disorders, and so
few investigators have been available, a major program of both
training and research has been directed to this area.

Progress was made this past year in basic research studies
of the nerve pathway by which the brain itself controls the sensi-
tivity of hearing. The arrangement of the nerve terminals and
manner of distribution within the ear have bean determined, and
illustrated by a plastic three-dimensional m~del which shows the
course and distribution of cochlear nerve fibers. Other con-
nections of the cochlear neucleus have been studied and two new
bundles of effectant nerve fibers have been identified. These

- 24 -
studies are increasing, our understanding of the brain's control over
the hearing process.

For the first time, investigators have described a mechan-
ism whereby nerve impulses in individual auditory nerve fibers
are initiated by receptor organs. Experiments with toatlly-deaf
"waltzing guinea pigs were instrumental in determining the source
of electrical potential within the cochlea.

Grant-supported research in this field covered a wide range
of research projects. One of these concerns otosclerosis, an
important cause of deafness, especially in the older age group.
In this disorder, the small bones of the inner ear, through which
sounds are normally transmitted, become rigidly fixed in position
and are no longer capable of transmission of the sound vibration.
The first approach to this disabling condition was the "stapes
mobilization operation." Through this procedure, the rigid bands
holding the bones were r&leased. The bones were then "mobilized,"
and in many instances considerable improvement was established.
An unfortunate feature of this procedure lies in the fact that
scar tissue may once again lead to the rigid fixation of these
structures. This year a new approach to this problem has been de-
veloped. This consists of by-passing the rigid bones with a very
thin plastic tube. Once accurately placed, the tube serves as a
channel for the transmission of the vibration directly to the sensi-
tive internal ear. The new plastic materials do not produce irritation

- 25 -

or inflammation of the tissues, and it appears that they may serve
as a permanent restorative for hearing in patients suffering from
this disorder.

During the past year, several new projects were supported in
the field of speech disorders and related subjects. In one such
study, investigators fabricated a larynx of tubing and were able
to film the various movements of this larynx. They suggest that
the shape of a thyroid muscle may determine the frequency of
vibration of the vocal cords.

In addition, the Institute's collaborative project includes
correlations of hearing and speech disorders with events of pregnancy
and labor. This program offers new opportunities in the speech and
hearing field.

TRAINING GRANTS

The unusual need for trained investigators in the area of
neurology, sensory disorders, and related disciplines has made it
imperative for the Institute to advance its training program as
rapidly as possible.

The Institute's training program has been in effect for
seven years and is now well established. During 1960, there
will be approximately 190 training programs providing training
for 930 trainees. Of the 930 individuals in training, a little
less than one-third or about 300 will complete training this
year.

- 26 -

Training is already well developed in clinical neurology
with 60 programs and in ophthalmology with 35 programs. No major
expansion is contemplated in these two areas. These programs,
however, need to be strengthened by placing greater emphasis on
the applicability of basic research methods to clinical problems.
There has been a need to develop scientists with knowledge of
basic research techniques who have the ability to bring these
talents to bear on the problems of neurological disease. There-
fore, most of the expansion in 1960 was in the basic science pro-
grams which now number 49. These include 6 in neurochemistry, 8
in neuroanatomy, 7 in neurophysiology, 8 in neuropharmacology,
15 in neuropathology, and 5 in sensory physiology.

Clinical otolaryngology is still behind other programs but
has expanded frcm 23 to 29 programs in 1960. To fill a continu-
ing need for pediatric neurologists, there are now 12 training
programs. Also, there are now 5 programs in medical audiology.

SPECIAL TRAINEESHIPS
The success of future research in solving the problems of
neurological and neuromuscular diseases, blindness, and deafness
will depend primarily upon the competence and investigative skills
of the basic scientists and clinicians being trained now for careers
in research. The complexity of the problems faced demands that this
training be specialized, diversified, and of the best quality to be
obtained anywhere in the world. Training support must therefore be
provided at advanced academic levels, beyond that ordinarily covered

- 27 -

by the Training Grant programs . Special Traineeships are proving to
be specially valuable as a means of fostering research careers for
those young men and woman who will form the backbone of our future
research program. Additionally, since investigative medicine is a
lifelong study, the Special Traineeship program is being utilized
by mature teacher-investigators to keep abreast of advances in their
individual fields of research interest.

Currently 207 trainees in 26 fields are in the Special
Traineeship program. Almost without exception, men who have com-
pleted such traineeships move rapidly into academic positions and
develop laboratories undertaking independent research.

RESEARCH FELLOWSHIPS

The purpose of the research fellowship program is to aid
young men and women who have manifested a desire for investigative
careers to become more expert by providing a part of the cost of
further academic training and research experience. If progress is
to be made in solving neurological and sensory disease problems,
the maintenance of a continuing supply of research manpower must
be assured. This program has proven to be an effective means of
achieving this objective, since more than 75 percent of those re-
ceiving training remain in research and teaching.

It is believed that the Research Fellowship funds available
now should be sufficient to meet the research training needs of
those whom it may be highly desirable to support in departments
where no training programs have been established.

- 28 -
INTERNATIONAL RESEARCH

Many scientists now believe that international studies could
hasten the answers to unsolved neurological and sensory disorders.
They are convinced that studies regarding the nature and frequency
of disease in relation to genetic and environmental factors in
diverse geographic regions and populations could add much to our
present store of scientific knowledge. With this thought in
mind, the Institute has established an office for international
neurological research programs in Antwerp, Belgium.

Under the direction of Dr. Pearce Bailey, the Institute's
former director, the program has two immediate aims. The first
is to survey, evaluate, and report on international scientific
talent and facilities for research and training in neurological
disorders. The second is to study and develop methods for the
application of this potential to the organization of promising
collaborative projects in international geographic clinical
pathology.

At the present time, two specific studies are considered
suitable for development: one relates to cerebrovascular diseases
and the other to disorders arising during pregnancy, birth, and
early infancy. The Institute's Advisory Council has recommended
the allocation of funds to the World Federation of Neurology
which has applied for a grant to develop a collaborative neuro-
pathological study of cerebrovascular diseases. A number of
European investigators have already expressed interest in re-
search relating to disorders arising in the perinatal period.

i-'.-fr

l-:', ■ ■ I

■()' :

- 29 -
In surveying and evaluating international neurological
talent and facilities, Dr. Bailey's liaison capacity with the
World Federation of Neurology and its professional societies
in more than forty countries will be helpful.

A TECHNICAL APPROACH TO NEUROLOGICAL PROBLEMS
A review of progress in recent years demonstrates the fre-
quency with which major medical discoveries have stemmed from
technological advances. Increasingly the medical scientist is
dependent upon the skills and techniques of the industrialist
and the technologist. The time has come when greater resources
from those of industry should be diverted toward the solution of
the important problems of national health. During the next year,
this Institute proposes to launch a determined campaign to acquaint
industry with medical problems relating to the brain and central
nervous system. It is hoped that industrial scientists from many
disciplines may bring new approaches to many unsolved problems.

SUMMARY OF RESEARCH ACCOMPLISHMENTS
The magnitude of the unsolved problems relating to neuro-
logical disorders could easily lead to discouragement and pessi-
mism. It is healthy, therefore, to consider the concrete achieve-
ments of the last five or ten years, noting that each has served
in some way to reduce the toll of misery and disability of these
dread disorders.

In the field of cerebral palsy, it is heartening to note
that kernicterus has been practically eliminated. This disorder,

- 30 -
which formerly accounted for more than one percent of all ad-
missions to our institutions for the mentally defective, did not
account for a single admission to one of our largest State
institutions over the last three years.

In the area of mental deficiency, the dietary treatment
of phenylketonuria, although not presenting the ideal solution
of this tragic problem, is already saving numerous victims from
hopeless idiocy. This is another condition which formerly ac-
counted for about one percent of admissions to our institutions
for the severely defective. Galactosemia and a new disorder--
"maple sugar" disease, also associated with abnormalities of body
chemistry, may also be amenable to dietary treatment.

Although not leading to direct elimination or cure, the dis-
covery of the chromosomal causes of Mongolism represents a tremendous
advance, and opens the way toward accurate knowledge of the causes
of this most important form of mental deficiency.

The last five years has seen the refinement of surgical
methods for the relief of involuntary movement. This has been
helpful not only for Parkinsonism but also for other bizarre forms
of movement and spasms.

In our campaign against blindness, retrolental fibroplasia
has been completely eliminated. The new technique of corneal trans-
plantation is bringing useful vision to many people whose lives
otherwise would have been spent in darkness. Drug therapy of
glaucoma, while not always effective, has tremendously reduced
the toll of blindness attributable to this disease.

.. (

'.It

- 31 -

There are encouraging reports of restoration of hearing in
patients suffering from otosclerosis. This form of deafness, prev-
alent in the older age groups, is rapidly yielding to newly devel-
oped surgical measures of relief.

Our techniques for the control of certain brain diseases
have also undergone great improvement. The use of the radioactive
tracer scanning technique for the localization of brain tumors has
simplified the early diagnosis of tumors, and is facilitating their
surgical removal. The development of new anesthetic agents, and
especially of hypothermia for brain operations, has caused a sharp
drop in the operative mortality of such conditions as cerebral
aneurysms and brain tumors . Ruptured cerebral aneurysm has in the
past carried with it a mortality of over 50 percent. In selected
cases, highly successful operative intervention is now feasible.

Training, also, has seen tremendous advances during this
period. In 1952, there were 15 training programs in clinical
neurology in 79 medical schools in the country. At that time there
were only 90 residents in training and about 250 qualified neurolo-
gists in the United States. Six states did not have a single
board-certified neurologist.

Today, with 85 medical schools this Institute has 60
training programs with 285 trainees in clinical neurology. There
are now 798 board-certified neurologists with qualified neurologists
in every state.

During the past year there has been a continued shift of
emphasis in the total research grants program, particularly in

- 32 -

the area of sensory disorders. Three years ago the Institute had
no research grants relating to disorders of speech. In 1959, there
were 17, and this year it is estimated that there will be 22. The
grants relating to hearing have also had a rapid growth with 49 in

1958, 57 in 1959, and an estimated 74 this year. From the early
founding of the Institute there have been research grants relating
to disorders of vision. This area, also, has grown the last two
years. There were 137 grants relating to vision in 1958, 200 in

1959, and an estimated 278 in 1960.

This rapid increase in not only quantity but quality of
research projects is a direct result of the Institute's training
program. It represents a strengthening of areas of research
previously neglected. It is anticipated that these trends
will continue in 1961.

In conclusion, Mr. Chairman, the appropriation request for
1961 is a total of $39,662,000 as compared with the appropriation
of $41,487,000 for 1960. This allowance for 1961 will provide for
the continuation of the I960 program levels in all activities and
will permit some increase in grants for research projects. It is
distributed among program activities as follows:

Grants :

Research projects-- $24,221,000

Research fellowships-- 536,000

Training - 7,339,000

- 33 -
Direct Operations :

Research ~ 6,371,000

Review and approval of grants 934,000

Training activities 50,000

Administration 211,000

TOTAL 39,662,000

OPENING STATEMENT
by
Associate Director, National Institutes of Health
Public Health Service

COMMITTEE ON APPROPRIATIONS

1961 ESTIMATE

for

Grants for Construction of Health Research Facilities 7

Mr. Chairman and Members of the Committee:

Now in its fourth year of operation, the Public Health service
program uhich provides grants to construct and equip health research
facilities v;as initially established as a three-year program through
the Health Research Facilities Act of 1956 (Title VII of the Public
Health Service Act, enacted as P.L. 335, 34th Congress). This
Act was extended for an additional three-year period by the 35th
Congress (P.L. 777) in August 1953. Initially, and under the
three-year extension, the Congress authorized appropriations of up to
$30,000,000 during each fiscal year to provide grants 'to nonfederal
public and nonprofit institutions for constructing and equipping
facilities for research in the sciences related to health.' Grants
are av7arded on a matching fund basis, uith the Federal share not to
exceed fifty percent of the costs for the research facilities
portion of such construction. The program is administered by the
Division of Research Grants of the National Institutes of Health.

- 2 -

Appropriations of $120,000,000 have been made by the Con-
gress during the first four program years--fiscal years 1957
through 1960. An appropriation of $25,000,000 is requested for
1961,

A requirement of the Research Facilities Act is that an
Annual Report be prepared, submitted to the President, and trans-
mitted to the Congress. The first three reports submitted in re-
sponse to this requirement have been printed as House Documents
21 and 324 of the 85th Congress, and House Document 73 of the
86th Congress. The Fourth and current report is being prepared
and will be referred to the Congress at this session of the 86th
Congress.

PROGRESS REPORT ON GRANTS AWARDED

Since the inception of this program a total of 872 new,
revised, and supplemental applications for construction grants
have been received. These requests for assistance in the construc-
tion of research facilities have been submitted by all types of
institutions engaged in various phases of health related research--
public and private nonprofit schools of medicine, dentistry,
osteopathy, and public health, as well as hospitals, universities,
and other research institutions. Up to the present time, the Sur-
geon General has awarded a total of 633 grants to 277 institutions
in 46 States and the District of Columbia. These grants represent
a total Federal expenditure of $118,210,963.

- 3 -

Seventy-two medical schools have received 199 grants
valued at $64,782,256; 15 dental schools have been awarded
$2,108,186 (16 grants); 5 schools of public health have received
7 grants in the total amount of $3,016,605; 2 schools of osteo-
pathy were awarded 2 grants, in the sum of $105,298; other schools
with research areas of interest to the Public Health Service, such
as those of veterinary medicine, pharmacy, chemistry and the bio-
logical sciences have been awarded 211 grants in the total amount
of $26,368,596; and other public and private nonprofit institu-
tions, hospitals and independent research institutions have re-
ceived 196 grants, valued at $21,830,022,

Construction progress . - During 1959, 147 projects were
completed and are in use. These facilities represent expendi-
tures of $15,983,118 in Federal funds and total construction costs
of more than $81 million. Some 180 additional projects currently
are under contract, representing Public Health Service grants in
the amount of $55,690,799,

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